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Haider AS, Ambatwar R, Khatik GL. Insights into PTP1B inhibitors as antidiabetic agents: Current research and future perspectives. Eur J Med Chem 2025; 295:117791. [PMID: 40460723 DOI: 10.1016/j.ejmech.2025.117791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 05/10/2025] [Accepted: 05/20/2025] [Indexed: 06/11/2025]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a well-established target for diabetes and obesity due to its involvement in the negative regulation of insulin signaling. It exerts this effect by dephosphorylating the insulin receptor (IR) and insulin receptor substrate (IRS), attenuating insulin activity. It is a protein tyrosine phosphatase (PTP) superfamily member, which includes a wide range of enzymes encoded by 107 distinct genes. The catalytic site of the PTP superfamily is positively charged and highly conserved among its members, which presents a significant challenge to developing inhibitors in terms of selectivity and oral bioavailability. T-cell protein tyrosine phosphatase (TCPTP), which plays a crucial role in the proliferation of T-cells and B-cells, is a close homologue of PTP1B, sharing 74 % sequence similarity within the catalytic domain. Although considerable efforts have been made to develop a selective and potent PTP1B inhibitor, no molecule has yet been developed as a drug. However, a few candidate compounds reached phase II clinical trials, but their further study was discontinued due to suboptimal efficacy and the manifestation of undesirable side effects. In this review, we aimed to decipher the complications associated with the PTP1B enzyme and the design strategies used by various research groups to develop small-molecule inhibitors, emphasising the structure-activity relationship of small molecules synthesized for this target. This review also delineates the molecular features, which will aid in designing rational approaches and foster further research into this target of type 2 diabetes mellitus.
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Affiliation(s)
- Abu Sahban Haider
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, 226002, India
| | - Ramesh Ambatwar
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, 226002, India
| | - Gopal L Khatik
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, 226002, India.
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2
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Kim G, Grams RJ, Hsu KL. Advancing Covalent Ligand and Drug Discovery beyond Cysteine. Chem Rev 2025. [PMID: 40404146 DOI: 10.1021/acs.chemrev.5c00001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Targeting intractable proteins remains a key challenge in drug discovery, as these proteins often lack well-defined binding pockets or possess shallow surfaces not readily addressed by traditional drug design. Covalent chemistry has emerged as a powerful solution for accessing protein sites in difficult to ligand regions. By leveraging activity-based protein profiling (ABPP) and LC-MS/MS technologies, academic groups and industry have identified cysteine-reactive ligands that enable selective targeting of challenging protein sites to modulate previously inaccessible biological pathways. Cysteines within a protein are rare, however, and developing covalent ligands that target additional residues hold great promise for further expanding the ligandable proteome. This review highlights recent advancements in targeting amino acids beyond cysteine binding with an emphasis on tyrosine- and lysine-directed covalent ligands and their applications in chemical biology and therapeutic development. We outline the process of developing covalent ligands using chemical proteomic methodology, highlighting recent successful examples and discuss considerations for future expansion to additional amino acid sites on proteins.
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Affiliation(s)
- Gibae Kim
- Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
| | - R Justin Grams
- Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
| | - Ku-Lung Hsu
- Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
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3
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Lin J, He R, Qu Z, Dong J, Krabill AD, Wu L, Bai Y, Conroy LR, Bruntz RC, Miao Y, Jassim BA, Babalola B, Nguele Meke FGB, Sun R, Gentry MS, Zhang ZY. Discovery and Evaluation of Active Site-Directed, Potent, and Selective Sulfophenyl Acetic Amide-Based Inhibitors for the Laforin Phosphatase. J Med Chem 2025; 68:9220-9240. [PMID: 40238926 DOI: 10.1021/acs.jmedchem.4c02580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Lafora disease is a rare and fatal progressive myoclonus epilepsy characterized by the accumulation of insoluble glycogen deposits in the brain and peripheral tissues. Mutations in the gene encoding the glycogen phosphatase laforin result in Lafora disease. Currently, there are no laforin-specific chemical probes, limiting our understanding of the roles of laforin in glycogen metabolism and other cellular processes. Here, we identified sulfophenyl acetic amide (SPAA), as a novel nonhydrolyzable phosphotyrosine mimetic for laforin inhibition. Using fragment-based and scaffold-hopping strategies, we discovered several highly potent and selective active site-directed laforin inhibitors. Among them, compound 9c displayed a Ki value of 1.9 ± 0.2 nM and more than 8300-fold preference for laforin. Moreover, these inhibitors efficiently block laforin-mediated glucan dephosphorylation inside the cell and possess favorable pharmacokinetic properties in mice. These chemical probes will enable further investigation of the roles of laforin in normal physiological processes and in diseases.
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Affiliation(s)
- Jianping Lin
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Rongjun He
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Zihan Qu
- The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | - Jiajun Dong
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Aaron D Krabill
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Li Wu
- Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Yunpeng Bai
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Lindsey R Conroy
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky 40506, United States
| | - Ronald C Bruntz
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506, United States
| | - Yiming Miao
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Brenson A Jassim
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Benjamin Babalola
- The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | | | - Ramon Sun
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, United States
- Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida 32610, United States
- McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, United States
| | - Matthew S Gentry
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, United States
- Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida 32610, United States
| | - Zhong-Yin Zhang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
- The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
- Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
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4
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Mu XY, Gao LX, Zhang ZX, Cao ZT, Cao Q, Zhang C, Li J, Xiang DJ, Zhou YB, Wang WL. Development of coumarin and procaine linked hybrid molecules as a novel class of SHP1 fluorescent activators. Eur J Med Chem 2025; 288:117394. [PMID: 39987836 DOI: 10.1016/j.ejmech.2025.117394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/11/2025] [Accepted: 02/11/2025] [Indexed: 02/25/2025]
Abstract
The development of small fluorescent organic molecules used in bioimaging experiment has boomed the progress of molecular and cellular biology, providing new and efficient tools to elucidate a myriad of cellular and multicellular processes. In this work, a class of fluorescent activators against SHP1 was designed and synthesized for the first time. The representative compound 3n showed activating effect against SHP1 with EC50 of 17.66 ± 1.48 μM and a fluorescence quantum yield of 0.521 in DMSO. Meanwhile, 3n showed good selectivity for SHP1, inhibited the proliferation of SU-DHL-2 cells and OCI-Ly10 cells with IC50 of 8.66 ± 1.26 μM and 9.16 ± 0.53 μM and exhibited potential for cellular imaging on human breast cancer cells.
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Affiliation(s)
- Xu-Yang Mu
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China; School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China
| | - Li-Xin Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Zhen-Xuan Zhang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China
| | - Zi-Tong Cao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Qing Cao
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Chun Zhang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Jia Li
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China
| | - Da-Jun Xiang
- Xishan People's Hospital of Wuxi City, Wuxi, Jiangsu, 214105, China.
| | - Yu-Bo Zhou
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China.
| | - Wen-Long Wang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China; School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China.
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5
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Li Q, Bai Y, Cavender SM, Miao Y, Nguele Meke F, Lasse-Opsahl EL, Zhu P, Doody GM, Tao WA, Zhang ZY. The PRL2 phosphatase up-regulates miR-21 through activation of the JAK2/STAT3 pathway to down-regulate the PTEN tumor suppressor. Biochem J 2025; 482:341-356. [PMID: 39665584 DOI: 10.1042/bcj20240626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/12/2024] [Indexed: 12/13/2024]
Abstract
The phosphatases of regenerating liver (PRLs) are members of the protein tyrosine phosphatase (PTP) superfamily that play pro-oncogenic roles in cell proliferation, migration, and survival. We previously demonstrated that PRLs can post-translationally down-regulate PTEN, a tumor suppressor frequently inactivated in human cancers, by dephosphorylating PTEN at Tyr336, which promotes the NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Here, we report that PRLs can also reduce PTEN expression by up-regulating microRNA-21 (miR-21), which is one of the most frequently overexpressed miRNAs in solid tumors. We observe a broad correlation between PRL and miR-21 levels in multiple human cancers. Mechanistically, PRL2, the most abundant and ubiquitously expressed PRL family member, promotes the JAK2/STAT3 pathway-mediated miR-21 expression by directly dephosphorylating JAK2 at Tyr570. Finally, we confirm that the PRL2-mediated miR-21 expression contributes to its oncogenic potential in breast cancer cells. Our study defines a new functional role of PRL2 in PTEN regulation through a miR-21-dependent post-transcriptional mechanism, in addition to our previously reported NEDD4-dependent post-translational PTEN regulation. Together, these studies further establish the PRLs as negative regulators of PTEN.
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Affiliation(s)
- Qinglin Li
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
- Current address: Thermo Fisher Scientific, 5781 Van Allen Way, Carlsbad, CA 92008, USA
| | - Yunpeng Bai
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Sarah M Cavender
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Yiming Miao
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Frederick Nguele Meke
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Emily L Lasse-Opsahl
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Peipei Zhu
- Department of Biochemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
| | - Gina M Doody
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, U.K
| | - W Andy Tao
- Department of Biochemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
- The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
- Purdue Institute for Cancer Research, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, U.S.A
- Purdue Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, U.S.A
| | - Zhong-Yin Zhang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
- The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, U.S.A
- Purdue Institute for Cancer Research, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, U.S.A
- Purdue Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, U.S.A
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6
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Ekambaram S, Arakelov G, Dokholyan NV. The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives. J Mol Biol 2025:169060. [PMID: 40043838 DOI: 10.1016/j.jmb.2025.169060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/26/2025] [Accepted: 02/26/2025] [Indexed: 03/16/2025]
Abstract
Protein allostery is a fundamental biological regulatory mechanism that allows communication between distant locations within a protein, modifying its function in response to signals. Experimental techniques, such as NMR spectroscopy and cryo-electron microscopy (cryo-EM), are critical validation tools for computational predictions and provide valuable insights into dynamic conformational changes. Combining these approaches has greatly improved our understanding of classical conformational allostery and complex dynamic coupling mechanisms. Recent advances in machine learning and enhanced sampling methods have broadened the scope of allostery research, identifying cryptic allosteric sites and directing new drug discovery approaches. Despite progress, bridging static structural data with dynamic functional states remains challenging. This review underscores the importance of combining experimental and computational approaches to comprehensively understand protein allostery and its diverse applications in biology and medicine.
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Affiliation(s)
- Srinivasan Ekambaram
- Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Grigor Arakelov
- Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, PA 17033, USA; Institute of Molecular Biology of the National Academy of Sciences of the Republic of Armenia, Yerevan 0014, Armenia
| | - Nikolay V Dokholyan
- Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Chemistry, Penn State University, University Park, PA 16802, USA; Department of Biomedical Engineering, Penn State University, University Park, PA 16802, USA.
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7
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Tao H, Yang B, Farhangian A, Xu K, Li T, Zhang ZY, Li J. Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds? J Med Chem 2025; 68:4040-4052. [PMID: 39937154 DOI: 10.1021/acs.jmedchem.4c02760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
Covalent-allosteric inhibitors (CAIs) may achieve the best of both worlds: increased potency, long-lasting effects, and reduced drug resistance typical of covalent ligands, along with enhanced specificity and decreased toxicity inherent in allosteric modulators. Therefore, CAIs can be an effective strategy to transform many undruggable targets into druggable ones. However, CAIs are challenging to design. In this perspective, we analyze the discovery of known CAIs targeting three protein families: protein phosphatases, protein kinases, and GTPases. We also discuss how computational methods and tools can play a role in addressing the practical challenges of rational CAI design.
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Affiliation(s)
- Hui Tao
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Bo Yang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Atena Farhangian
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Ke Xu
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Tongtong Li
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Zhong-Yin Zhang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Jianing Li
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
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8
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Montuschi P, Adcock IM. Protein tyrosine phosphatase 4A3 inhibition: A new pharmacological strategy for acute lung injury? J Pharmacol Exp Ther 2025; 392:100045. [PMID: 39969271 DOI: 10.1016/j.jpet.2024.100045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 10/03/2024] [Indexed: 02/20/2025] Open
Affiliation(s)
- Paolo Montuschi
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Roma, Italy.
| | - Ian M Adcock
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
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9
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Shetty SR, Kar T, Das A. Epidermal growth factor receptor mutations in breast Cancer: Therapeutic challenges and way forward. Bioorg Chem 2025; 154:108037. [PMID: 39672077 DOI: 10.1016/j.bioorg.2024.108037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is upregulated in aggressive triple-negative breast cancer (TNBC). Ligands such as EGF, TGF-α, epigen, and amphiregulin activate the auto-phosphorylation activity of tyrosine residues on EGFR, which regulates the growth, proliferation, adhesion, migration, and survival of cancer cells. Our prior studies depicted that inhibition of EGFR modulates the chemosensitivity in breast cancer stem cells and, thus, serves as a potent therapeutic target in breast cancer. Small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) specifically targeting EGFR have been clinically approved for breast cancer treatment. However, intrinsic and acquired resistance generated due to EGFR mutations limits the applications of designed EGFR-TKIs in breast cancer patients. This review highlights the therapeutic approaches, and the challenges encountered in targeting EGFR-specific mutations. It suggests the need to develop more advanced higher-generation inhibitors for use in combinatorial therapy along with chemo-or-immune therapeutics in clinics as a breast cancer treatment strategy against relapse of the disease.
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Affiliation(s)
- Swathi R Shetty
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Trisha Kar
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Amitava Das
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India.
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10
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Lazo JS, Isbell KN, Vasa SA, Llaneza DC, Mingledorff GA, Sharlow ER. Deletion of PTP4A3 phosphatase in high-grade serous ovarian cancer cells decreases tumorigenicity and produces marked changes in intracellular signaling pathways and cytokine release. J Pharmacol Exp Ther 2025; 392:100010. [PMID: 39892999 DOI: 10.1124/jpet.124.002110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/28/2024] [Accepted: 04/01/2024] [Indexed: 04/07/2024] Open
Abstract
The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and extracellular signal-regulated kinase. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3, to assess their tumorigenicity, to examine their cellular phenotype, and to uncover changes in their intracellular signaling pathways and cytokine release profiles. Genetic deletion of PTP4A3 using CRISPR/CRISPR-associated protein 9 enabled the generation of individual clones derived from single cells isolated from the polyclonal knockout population. We observed a >90% depletion of PTP4A3 protein levels by western blotting in the clonal cell lines compared with the sham-transfected wild-type population. The wild-type and polyclonal knockout cell lines shared similar monolayer growth rates, whereas the isolated clonal populations 2B4, 3C9, and 3C12 exhibited significantly lower monolayer growth characteristics consistent with their lower PTP4A3 levels. The clonal Ptp4a3 knockout cell lines also had substantially lower in vitro colony formation efficiencies compared with the wild-type cells and were less tumorigenic in vivo. The clonal knockout cells were markedly less responsive to interleukin-6-stimulated migration in a scratch wound assay compared with the wild-type cells. Antibody microarray assays documented differences in cytokine release and intracellular phosphorylation patterns in the Ptp4a3-deleted clones. Bioinformatic network analyses indicated alterations in cellular signaling nodes. These biochemical changes could ultimately form the foundation for pharmacodynamic endpoints useful for emerging anti-PTP4A3 therapeutics. SIGNIFICANCE STATEMENT: Clones of high-grade serous ovarian cancer cells were isolated, in which the oncogenic phosphatase Ptp4a3 gene was deleted using CRISPR/CRISPR-associated protein 9 methodologies. The Ptp4a3-null cells exhibited loss of in vitro proliferation, colony formation, and migration and reduced in vivo tumorigenesis. Marked differences in intracellular protein phosphorylation and cytokine release were seen. The newly developed Ptp4a3 knockout cells should provide useful tools to probe the role of PTP4A3 phosphatase in ovarian cancer cell survival, tumorigenicity, and cell signaling.
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Affiliation(s)
- John S Lazo
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia; KeViRx, Inc., Charlottesville, Virginia.
| | | | | | - Danielle C Llaneza
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia
| | | | - Elizabeth R Sharlow
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia; KeViRx, Inc., Charlottesville, Virginia
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11
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Xia CC, Chen HT, Deng H, Huang YT, Xu GQ. Reactive oxygen species and oxidative stress in acute pancreatitis: Pathogenesis and new therapeutic interventions. World J Gastroenterol 2024; 30:4771-4780. [PMID: 39649547 PMCID: PMC11606378 DOI: 10.3748/wjg.v30.i45.4771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 09/27/2024] [Accepted: 10/29/2024] [Indexed: 11/13/2024] Open
Abstract
Acute pancreatitis (AP) is a common acute gastrointestinal disorder affecting approximately 20% of patients with systemic inflammatory responses that may cause pancreatic and peripancreatic fat necrosis. This condition often progresses to multiple organ failure, significantly increasing morbidity and mortality. Oxidative stress, characterized by an imbalance between the body's reactive oxygen species (ROS) and antioxidants, activates the inflammatory signaling pathways. Although the pathogenesis of AP is not fully understood, ROS are increasingly recognized as critical in the disease's progression and development. Modulating the oxidative stress pathway has shown efficacy in mitigating the progression of AP. Despite numerous basic studies examining this pathway, comprehensive reviews of recent research remain sparse. This systematic review offers an in-depth examination of the critical role of oxidative stress in the pathogenesis and progression of AP and evaluates the therapeutic potential of antioxidant interventions in its management.
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Affiliation(s)
- Chuan-Chao Xia
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Tan Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hao Deng
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Ting Huang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Guo-Qiang Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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12
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Bharathidasan D, Maity C. Organelle-Specific Smart Supramolecular Materials for Bioimaging and Theranostics Application. Top Curr Chem (Cham) 2024; 383:1. [PMID: 39607460 DOI: 10.1007/s41061-024-00483-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 11/04/2024] [Indexed: 11/29/2024]
Abstract
In cellular environments, certain synthetic molecules can form nanostructures via self-assembly, impacting molecular imaging, and biomedical applications. Control over the formation of these self-assembled nanostructures in subcellular organelle is challenging. By the action of stimuli, either present in the cellular environment or applied externally, in situ generation of molecular precursors can lead to accumulation and supramolecular nanostructure formation, resulting in efficient bioimaging. Here, we summarize smart fluorophore-based ordered nanostructure preparation at specific organelles for efficient bioimaging and therapeutic application towards cancer theranostics. We also present challenges and an outlook regarding intercellular self-assembly for theranostics application. Altogether, smart nanostructured materials with fluorescence read-outs at specific subcellular compartments would be beneficial in synthetic biology and precision therapeutics.
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Affiliation(s)
- Dineshkumar Bharathidasan
- (Organic)Material Science and Engineering Laboratory, Centre for Nanobiotechnology (CNBT), Vellore Institute of Technology (VIT), Vellore Campus, Vellore, Tamilnadu, 632014, India
| | - Chandan Maity
- (Organic)Material Science and Engineering Laboratory, Centre for Nanobiotechnology (CNBT), Vellore Institute of Technology (VIT), Vellore Campus, Vellore, Tamilnadu, 632014, India.
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13
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Han C, Fu S, Chen M, Gou Y, Liu D, Zhang C, Huang X, Xiao L, Zhao M, Zhang J, Xiao Q, Peng D, Xue Y. GPSD: a hybrid learning framework for the prediction of phosphatase-specific dephosphorylation sites. Brief Bioinform 2024; 26:bbae694. [PMID: 39749667 PMCID: PMC11695897 DOI: 10.1093/bib/bbae694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 01/04/2025] Open
Abstract
Protein phosphorylation is dynamically and reversibly regulated by protein kinases and protein phosphatases, and plays an essential role in orchestrating a wide range of biological processes. Although a number of tools have been developed for predicting kinase-specific phosphorylation sites (p-sites), computational prediction of phosphatase-specific dephosphorylation sites remains to be a great challenge. In this study, we manually curated 4393 experimentally identified site-specific phosphatase-substrate relationships for 3463 dephosphorylation sites occurring on phosphoserine, phosphothreonine, and/or phosphotyrosine residues, from the literature and public databases. Then, we developed a hybrid learning framework, the group-based prediction system for the prediction of phosphatase-specific dephosphorylation sites (GPSD). For model training, we integrated 10 types of sequence features and utilized three types of machine learning methods, including penalized logistic regression, deep neural networks, and transformer neural networks. First, a pretrained model was constructed using 561 416 nonredundant p-sites and then fine-tuned to generate computational models for predicting general dephosphorylation sites. In addition, 103 individual phosphatase-specific predictors were constructed via transfer learning and meta-learning. For site prediction, one or multiple protein sequences in FASTA format could be inputted, and the prediction results will be shown together with additional annotations, such as protein-protein interactions, structural information, and disorder propensity. The online service of GPSD is freely available at https://gpsd.biocuckoo.cn/. We believe that GPSD can serve as a valuable tool for further analysis of dephosphorylation.
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Affiliation(s)
- Cheng Han
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Shanshan Fu
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Miaomiao Chen
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Yujie Gou
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Dan Liu
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Chi Zhang
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Xinhe Huang
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Leming Xiao
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Miaoying Zhao
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Jiayi Zhang
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Qiang Xiao
- School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Di Peng
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
| | - Yu Xue
- Department of Bioinformatics and Systems Biology, MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, Hubei 430074, China
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14
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Solopov PA, Colunga Biancatelli RML, Day T, Gregory B, Sharlow ER, Lazo JS, Catravas JD. KVX-053, a protein tyrosine phosphatase 4A3 inhibitor, ameliorates SARS-CoV-2 spike protein subunit 1-induced acute lung injury in mice. J Pharmacol Exp Ther 2024; 392:100022. [PMID: 39969268 DOI: 10.1124/jpet.124.002154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 08/26/2024] Open
Abstract
Acute respiratory distress syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of proinflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in patients with COVID-19. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to lung angiotensin-converting enzyme 2 (ACE2), and in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long-COVID. Protein tyrosine phosphatase (PTP) 4A3 is a key mediator of ARDS pathology. This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19-associated ALI. Intratracheal administration of SARS-CoV-2 spike protein subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines, structural lung injury, and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings provide the first evidence supporting a role for PTP4A3 in the development of SARS-CoV-2-mediated ALI. SIGNIFICANCE STATEMENT: This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19-associated ALI/ARDS. Intratracheal administration of SARS-CoV-2 spike protein subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines and chemokines, structural lung injury, and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings suggest that this novel PTP4A3 inhibitor may be useful against COVID-19 and potentially other viral-induced ARDS.
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Affiliation(s)
- Pavel A Solopov
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia.
| | | | - Tierney Day
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia
| | - Betsy Gregory
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia
| | - Elizabeth R Sharlow
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia; KeViRx Inc, Charlottesville, Virginia
| | - John S Lazo
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia; KeViRx Inc, Charlottesville, Virginia
| | - John D Catravas
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia; School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, Virginia
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15
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Tang Y, Liu X, Qi P, Cai Y, Wang H, Qin Y, Gu W, Wang C, Sun Y, Zhu C. Single-Atom Ce-Doped Metal Hydrides with High Phosphatase-like Activity Amplify Oxidative Stress-Induced Tumor Apoptosis. ACS NANO 2024; 18:25685-25694. [PMID: 39223090 DOI: 10.1021/acsnano.4c07851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Phosphates within tumors function as key biomolecules, playing a significant role in sustaining the viability of tumors. To disturb the homeostasis of cancer cells, regulating phosphate within the organism proves to be an effective strategy. Herein, we report single-atom Ce-doped Pt hydrides (Ce/Pt-H) with high phosphatase-like activity for phosphate hydrolysis. The resultant Ce/Pt-H exhibits a 26.90- and 6.25-fold increase in phosphatase-like activity in comparison to Ce/Pt and Pt-H, respectively. Mechanism investigations elucidate that the Ce Lewis acid site facilitates the coordination with phosphate groups, while the surface hydrides enhance the electron density of Pt for promoting catalytic ability in H2O cleavage and subsequent nucleophilic attack of hydroxyl groups. Finally, by leveraging its phosphatase-like activity, Ce/Pt-H can effectively regulate intracellular phosphates to disrupt redox homeostasis and amplify oxidative stress within cancer cells, ultimately leading to tumor apoptosis. This work provides fresh insights into noble-metal-based phosphatase mimics for inducing tumor apoptosis.
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Affiliation(s)
- Yinjun Tang
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Xupeng Liu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Pengcheng Qi
- Institute of Nano-Science and Technology, College of Physical Science and Technology, Central China Normal University, Wuhan 430079, P. R. China
| | - Yujia Cai
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Hengjia Wang
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Ying Qin
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Wenling Gu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Canglong Wang
- Institute of Modern Physics, Chinese Academy of Science, Lanzhou 730000, P. R. China
| | - Yao Sun
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Chengzhou Zhu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
- College of Material Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou 311121, P. R. China
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16
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Ma Q, He X, Wang X, Zhao G, Zhang Y, Su C, Wei M, Zhang K, Liu M, Zhu Y, He J. PTPN14 aggravates neointimal hyperplasia via boosting PDGFRβ signaling in smooth muscle cells. Nat Commun 2024; 15:7398. [PMID: 39191789 PMCID: PMC11350182 DOI: 10.1038/s41467-024-51881-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 08/20/2024] [Indexed: 08/29/2024] Open
Abstract
Smooth muscle cell (SMC) phenotypic modulation, primarily driven by PDGFRβ signaling, is implicated in occlusive cardiovascular diseases. However, the promotive and restrictive regulation mechanism of PDGFRβ and the role of protein tyrosine phosphatase non-receptor type 14 (PTPN14) in neointimal hyperplasia remain unclear. Our study observes a marked upregulation of PTPN14 in SMCs during neointimal hyperplasia. PTPN14 overexpression exacerbates neointimal hyperplasia in a phosphatase activity-dependent manner, while SMC-specific deficiency of PTPN14 mitigates this process in mice. RNA-seq indicates that PTPN14 deficiency inhibits PDGFRβ signaling-induced SMC phenotypic modulation. Moreover, PTPN14 interacts with intracellular region of PDGFRβ and mediates its dephosphorylation on Y692 site. Phosphorylation of PDGFRβY692 negatively regulates PDGFRβ signaling activation. The levels of both PTPN14 and phospho-PDGFRβY692 are correlated with the degree of stenosis in human coronary arteries. Our findings suggest that PTPN14 serves as a critical modulator of SMCs, promoting neointimal hyperplasia. PDGFRβY692, dephosphorylated by PTPN14, acts as a self-inhibitory site for controlling PDGFRβ activation.
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MESH Headings
- Animals
- Humans
- Male
- Mice
- Coronary Vessels/pathology
- Coronary Vessels/metabolism
- Hyperplasia/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Neointima/metabolism
- Neointima/pathology
- Phosphorylation
- Protein Tyrosine Phosphatases, Non-Receptor/metabolism
- Protein Tyrosine Phosphatases, Non-Receptor/genetics
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Receptor, Platelet-Derived Growth Factor beta/genetics
- Signal Transduction
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Affiliation(s)
- Qiannan Ma
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
- Department of Endocrinology and Metabolism, Tianjin Research Institute of Endocrinology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xue He
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
| | - Xue Wang
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
| | - Guobing Zhao
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
| | - Yanhong Zhang
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
| | - Chao Su
- Division of Cardiovascular Surgery, Cardiac and Vascular Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518040, China
| | - Minxin Wei
- Division of Cardiovascular Surgery, Cardiac and Vascular Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518040, China
| | - Kai Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ming Liu
- Department of Endocrinology and Metabolism, Tianjin Research Institute of Endocrinology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Yi Zhu
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
- Department of Endocrinology and Metabolism, Tianjin Research Institute of Endocrinology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Jinlong He
- Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
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17
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Miao Y, Bai Y, Miao J, Murray AA, Lin J, Dong J, Qu Z, Zhang RY, Nguyen QD, Wang S, Yu J, Nguele Meke F, Zhang ZY. Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven cancers. J Clin Invest 2024; 134:e177142. [PMID: 38842946 PMCID: PMC11291269 DOI: 10.1172/jci177142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 06/04/2024] [Indexed: 08/02/2024] Open
Abstract
Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.
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Affiliation(s)
- Yiming Miao
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | - Jinmin Miao
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | | | - Jianping Lin
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | - Jiajun Dong
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | - Zihan Qu
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA
| | - Ruo-Yu Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | - Quyen D. Nguyen
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA
| | - Shaomeng Wang
- Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Jingmei Yu
- Department of Medicinal Chemistry and Molecular Pharmacology and
| | | | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology and
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA
- Institute for Cancer Research and
- Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
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18
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Zhang C, Yang X, Wu L, Liu F, Dong K, Guo C, Gong L, Dong G, Shi Y, Gu Z, Liu X, Liu S, Wu J, Su F. Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity. ACS Pharmacol Transl Sci 2024; 7:1426-1437. [PMID: 38751623 PMCID: PMC11091969 DOI: 10.1021/acsptsci.4c00054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 05/18/2024]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship. The screened analogues S2, S6, A2-14, A2-17, A2-20, and A2-21 exhibited an improved PTP1B/TC-PTP dual inhibitory activity and achieved good stability in the plasma of mice and dogs, which indicated long-acting potential. In mouse models of type 2 diabetes mellitus (T2DM), the selected analogues S6, S7, A2-20, and A2-21 with an excellent target activity and plasma stability generated once-weekly therapeutic potency for T2DM at lower dosage (0.5 μmol/kg). In addition, evidence was provided to confirm the cell permeability and targeted enrichment of the BimBH3 analogues. In summary, we report here that site-specific modification and long fatty acid conjugation afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced stability, in vivo activity, and long-acting pharmacokinetic profile. Our findings could guide the further optimization of BimBH3 analogues and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new therapeutic approach for T2DM, which may facilitate the discovery and development of alternative once-weekly anti-T2DM drug candidates.
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Affiliation(s)
- Chuanliang Zhang
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Xianmin Yang
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Lijuan Wu
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Fei Liu
- Joincare
Pharmaceutical Group Industry Co., Ltd, Shenzhen 518000, China
| | - Kehong Dong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Chuanlong Guo
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Liyan Gong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Guozhen Dong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Yiying Shi
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Zongwen Gu
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Xiaochun Liu
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Shan Liu
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Juan Wu
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Feng Su
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
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19
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Perez-Quintero LA, Abidin BM, Tremblay ML. Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP. Front Med (Lausanne) 2024; 11:1364778. [PMID: 38707187 PMCID: PMC11066278 DOI: 10.3389/fmed.2024.1364778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/27/2024] [Indexed: 05/07/2024] Open
Abstract
In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.
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Affiliation(s)
- Luis Alberto Perez-Quintero
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Belma Melda Abidin
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Michel L. Tremblay
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
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20
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Miao J, Zhang ZY. Drugging Protein Tyrosine Phosphatases through Targeted Protein Degradation. ChemMedChem 2024; 19:e202300669. [PMID: 38233347 PMCID: PMC11021144 DOI: 10.1002/cmdc.202300669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/22/2023] [Accepted: 01/17/2024] [Indexed: 01/19/2024]
Abstract
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that regulate protein tyrosine phosphorylation levels of a large variety of proteins in cells. Anomalies in protein tyrosine phosphorylation have been associated with the development of numerous human diseases, leading to a heightened interest in PTPs as promising targets for drug development. However, therapeutic targeting of PTPs has faced skepticism about their druggability. Besides the conventional small molecule inhibitors, proteolysis-targeting chimera (PROTAC) technology offers an alternative approach to target PTPs. PROTAC molecules utilize the ubiquitin-proteasome system to degrade specific proteins and have unique advantages compared with inhibitors: 1) PROTACs are highly efficient and can work at much lower concentrations than that expected based on their biophysical binding affinity; 2) PROTACs may achieve higher selectivity for the targeted protein than that dictated by their binding affinity alone; and 3) PROTACs may engage any region of the target protein in addition to the functional site. This review focuses on the latest advancement in the development of targeted PTP degraders and deliberates on the obstacles and prospective paths of harnessing this technology for therapeutic targeting of the PTPs.
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Affiliation(s)
- Jinmin Miao
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
| | - Zhong-Yin Zhang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
- Department of Chemistry, 560 Oval Drive, West Lafayette, IN 47907, USA
- Institute for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, IN 47907, USA
- Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
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21
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Lin P, Zhang B, Yang H, Yang S, Xue P, Chen Y, Yu S, Zhang J, Zhang Y, Chen L, Fan C, Li F, Ling D. An artificial protein modulator reprogramming neuronal protein functions. Nat Commun 2024; 15:2039. [PMID: 38448420 PMCID: PMC10917760 DOI: 10.1038/s41467-024-46308-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 02/14/2024] [Indexed: 03/08/2024] Open
Abstract
Reversible protein phosphorylation, regulated by protein phosphatases, fine-tunes target protein function and plays a vital role in biological processes. Dysregulation of this process leads to aberrant post-translational modifications (PTMs) and contributes to disease development. Despite the widespread use of artificial catalysts as enzyme mimetics, their direct modulation of proteins remains largely unexplored. To address this gap and enable the reversal of aberrant PTMs for disease therapy, we present the development of artificial protein modulators (APROMs). Through atomic-level engineering of heterogeneous catalysts with asymmetric catalytic centers, these modulators bear structural similarities to protein phosphatases and exhibit remarkable ability to destabilize the bridging μ3-hydroxide. This activation of catalytic centers enables spontaneous hydrolysis of phospho-substrates, providing precise control over PTMs. Notably, APROMs, with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein by directly hydrolyzing hyperphosphorylated α-synuclein. Consequently, synaptic function is reinforced in Parkinson's disease. Our findings offer a promising avenue for reprogramming protein function through de novo PTMs strategy.
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Affiliation(s)
- Peihua Lin
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Center for Translational Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, 200240, China
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Zhang
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Center for Translational Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, 200240, China
- World Laureates Association (WLA) Laboratories, Shanghai, 201210, China
| | - Hongli Yang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shengfei Yang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Pengpeng Xue
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ying Chen
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shiyi Yu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jichao Zhang
- Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China
| | - Yixiao Zhang
- In-situ Center for Physical Sciences, School of Chemistry and Chemical Engineering, Shanghai Electrochemical Energy Device Research Center (SEED), Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Liwei Chen
- In-situ Center for Physical Sciences, School of Chemistry and Chemical Engineering, Shanghai Electrochemical Energy Device Research Center (SEED), Shanghai Jiao Tong University, Shanghai, 200240, China
- Future Battery Research Center, Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chunhai Fan
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Center for Translational Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Fangyuan Li
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, 310009, China.
| | - Daishun Ling
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Center for Translational Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, 200240, China.
- World Laureates Association (WLA) Laboratories, Shanghai, 201210, China.
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22
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Zou J, Qin Z, Li R, Yan X, Huang H, Yang B, Zhou F, Zhang L. iProPhos: A Web-Based Interactive Platform for Integrated Proteome and Phosphoproteome Analysis. Mol Cell Proteomics 2024; 23:100693. [PMID: 38097182 PMCID: PMC10828474 DOI: 10.1016/j.mcpro.2023.100693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/06/2023] [Accepted: 12/11/2023] [Indexed: 01/29/2024] Open
Abstract
Large-scale omics studies have generated a wealth of mass spectrometry-based proteomics data, which provide additional insights into disease biology spanning genomic boundaries. However, there is a notable lack of web-based analysis and visualization tools that facilitate the reutilization of these data. Given this challenge, we present iProPhos, a user-friendly web server to deliver interactive and customizable functionalities. iProPhos incorporates a large number of samples, including 1444 tumor samples and 746 normal samples across 12 cancer types, sourced from the Clinical Proteomic Tumor Analysis Consortium. Additionally, users can also upload their own proteomics/phosphoproteomics data for analysis and visualization. In iProPhos, users can perform profiling plotting and differential expression, patient survival, clinical feature-related, and correlation analyses, including protein-protein, mRNA-protein, and kinase-substrate correlations. Furthermore, functional enrichment, protein-protein interaction network, and kinase-substrate enrichment analyses are accessible. iProPhos displays the analytical results in interactive figures and tables with various selectable parameters. It is freely accessible at http://longlab-zju.cn/iProPhos without login requirement. We present two case studies to demonstrate that iProPhos can identify potential drug targets and upstream kinases contributing to site-specific phosphorylation. Ultimately, iProPhos allows end-users to leverage the value of big data in cancer proteomics more effectively and accelerates the discovery of novel therapeutic targets.
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Affiliation(s)
- Jing Zou
- The Second Affiliated Hospital and Life Sciences Institute and School of Medicine, The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, China
| | - Ziran Qin
- The Second Affiliated Hospital and Life Sciences Institute and School of Medicine, The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, China
| | - Ran Li
- School of Medicine, Hangzhou City University, Hangzhou, China.
| | - Xiaohua Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Huizhe Huang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bing Yang
- The Second Affiliated Hospital and Life Sciences Institute and School of Medicine, The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, China; Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Fangfang Zhou
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
| | - Long Zhang
- The Second Affiliated Hospital and Life Sciences Institute and School of Medicine, The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
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23
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Qu Z, Krabill AD, Zhang ZY. High-Throughput Discovery and Characterization of Covalent Inhibitors for Protein Tyrosine Phosphatases. Methods Mol Biol 2024; 2743:301-316. [PMID: 38147223 DOI: 10.1007/978-1-0716-3569-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Covalent inhibition has gained increasing interest in targeting the undruggable protein tyrosine phosphatases (PTPs). However, a systematic method for discovering and characterizing covalent PTP inhibitors has yet to be established. Here, we describe a workflow involving high-throughput screening of covalent fragment libraries and a novel biochemical assay that enables the acquisition of kinetics parameters of PTP inhibition by covalent inhibitors with higher throughput.
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Affiliation(s)
- Zihan Qu
- Department of Chemistry, Purdue University, West Lafayette, IN, USA
| | - Aaron D Krabill
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
| | - Zhong-Yin Zhang
- Department of Chemistry, Purdue University, West Lafayette, IN, USA.
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
- Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
- Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
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24
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Carlock C, Bai Y, Paige-Hood A, Li Q, Nguele Meke F, Zhang ZY. PRL2 inhibition elevates PTEN protein and ameliorates progression of acute myeloid leukemia. JCI Insight 2023; 8:e170065. [PMID: 37665633 PMCID: PMC10619439 DOI: 10.1172/jci.insight.170065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 08/23/2023] [Indexed: 09/06/2023] Open
Abstract
Overexpression of phosphatases of regenerating liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in patients with acute myeloid leukemia (AML). In the current study, a PTEN-knockdown AML animal model was generated to assess the effect of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the BM niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN and downregulation of AKT/mTOR-regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.
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Affiliation(s)
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology
| | | | - Qinglin Li
- Department of Medicinal Chemistry and Molecular Pharmacology
| | | | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology
- Department of Chemistry
- Institute for Cancer Research, and
- Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
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25
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Liang X, Zhao H, Du J, Li X, Li K, Zhao Z, Bi W, Zhang X, Yu D, Zhang J, Fang H, Hou X. Discovery of benzofuran-2-carboxylic acid derivatives as lymphoid tyrosine phosphatase (LYP) inhibitors for cancer immunotherapy. Eur J Med Chem 2023; 258:115599. [PMID: 37399712 DOI: 10.1016/j.ejmech.2023.115599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/14/2023] [Accepted: 06/24/2023] [Indexed: 07/05/2023]
Abstract
Lymphoid-tyrosine phosphatase (LYP) is mainly expressed in the immune system and plays an important role in the T-cell receptor (TCR) signaling pathway and tumor immunity. Herein, we identify benzofuran-2-carboxylic acid as a potent pTyr mimic and design a new series of new LYP inhibitors. The most active compound, D34 and D14, reversibly inhibits LYP (Ki = 0.93 μM and 1.34 μM) and possess a certain degree of selectivity toward other phosphatases. Meanwhile, D34 and D14 regulate the TCR signaling by specifically inhibiting LYP. In particular, D34 and D14 significantly suppress tumor growth in an MC38 syngeneic mouse model by boosting antitumor immunity, including activation of T-cell and inhibition of M2 macrophage polarization. Moreover, treatment of D34 or D14 upregulate PD-1/PD-L1 expression, which can be leveraged with PD-1/PD-L1 inhibition to augment immunotherapy. In summary, our study demonstrates the feasibility of targeting LYP for cancer immunotherapy and provides new lead compounds for further drug development.
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Affiliation(s)
- Xiao Liang
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China; Department of Pharmacy, Qilu Hospital of Shandong University, Ji'nan, Shandong, 250012, China
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, and Key Laboratory of Chemical Biology of Natural Pro ducts (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Jintong Du
- Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, Shandong, 250117, China
| | - Xue Li
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Kangshuai Li
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Zhongcheng Zhao
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Wenchao Bi
- Institute of Immunopharmaceutical Sciences, and Key Laboratory of Chemical Biology of Natural Pro ducts (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Xiaotong Zhang
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Dian Yu
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, and Key Laboratory of Chemical Biology of Natural Pro ducts (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Hao Fang
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Xuben Hou
- Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China.
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26
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Shu L, Du C, Zuo Y. Abnormal phosphorylation of protein tyrosine in neurodegenerative diseases. J Neuropathol Exp Neurol 2023; 82:826-835. [PMID: 37589710 DOI: 10.1093/jnen/nlad066] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis, are chronic disorders of the CNS that are characterized by progressive neuronal dysfunction. These diseases have diverse clinical and pathological features and their pathogenetic mechanisms are not yet fully understood. Currently, widely accepted hypotheses include the accumulation of misfolded proteins, oxidative stress from reactive oxygen species, mitochondrial dysfunction, DNA damage, neurotrophin dysfunction, and neuroinflammatory processes. In the CNS of patients with neurodegenerative diseases, a variety of abnormally phosphorylated proteins play important roles in pathological processes such as neuroinflammation and intracellular accumulation of β-amyloid plaques and tau. In recent years, the roles of abnormal tyrosine phosphorylation of intracellular signaling molecules regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) in neurodegenerative diseases have attracted increasing attention. Here, we summarize the roles of signaling pathways related to protein tyrosine phosphorylation in the pathogenesis of neurodegenerative diseases and the progress of therapeutic studies targeting PTKs and PTPs that provide theoretical support for future studies on therapeutic strategies for these devastating and important neurodegenerative diseases.
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Affiliation(s)
- Lijuan Shu
- Department of Anesthesiology, West China Hospital, Sichuan University & The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- Department of Obstetrics and Gynecology Intensive Care Unit, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Chunfu Du
- Department of Neurosurgery, Ya'an People's Hospital, Ya'an, China
| | - Yunxia Zuo
- Department of Anesthesiology, West China Hospital, Sichuan University & The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, China
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27
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Lazo JS, Colunga-Biancatelli RML, Solopov PA, Catravas JD. An acute respiratory distress syndrome drug development collaboration stimulated by the Virginia Drug Discovery Consortium. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2023; 28:249-254. [PMID: 36796645 PMCID: PMC9930264 DOI: 10.1016/j.slasd.2023.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023]
Abstract
The genesis of most older medicinal agents has generally been empirical. During the past one and a half centuries, at least in the Western countries, discovering and developing drugs has been primarily the domain of pharmaceutical companies largely built upon concepts emerging from organic chemistry. Public sector funding for the discovery of new therapeutics has more recently stimulated local, national, and international groups to band together and focus on new human disease targets and novel treatment approaches. This Perspective describes one contemporary example of a newly formed collaboration that was simulated by a regional drug discovery consortium. University of Virginia, Old Dominion University, and a university spinout company, KeViRx, Inc., partnered under a NIH Small Business Innovation Research grant, to produce potential therapeutics for acute respiratory distress syndrome resulting from the ongoing COVID-19 pandemic.
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Affiliation(s)
- John S Lazo
- Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, VA, USA.
| | | | - Pavel A Solopov
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA
| | - John D Catravas
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA
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28
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Asano W, Yamanaka K, Ohara Y, Uhara T, Doi S, Orita T, Iwanaga T, Adachi T, Fujioka S, Akaki T, Ikegashira K, Hantani Y. Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques. Biochemistry 2023. [PMID: 37414577 DOI: 10.1021/acs.biochem.3c00079] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Tyrosine phosphorylation is an essential post-translational modification that regulates various biological events and is implicated in many diseases including cancer and atherosclerosis. Vascular endothelial protein tyrosine phosphatase (VE-PTP), which plays an important role in vascular homeostasis and angiogenesis, is therefore an attractive drug target for these diseases. However, there are still no drugs targeting PTP including VE-PTP. In this paper, we report the discovery of a novel VE-PTP inhibitor, Cpd-2, by fragment-based screening combining various biophysical techniques. Cpd-2 is the first VE-PTP inhibitor with a weakly acidic structure and high selectivity, unlike known strongly acidic inhibitors. We believe that this compound represents a new possibility for the development of bioavailable VE-PTP inhibitors.
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Affiliation(s)
- Wataru Asano
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Kenji Yamanaka
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Yasunori Ohara
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Toru Uhara
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Satoki Doi
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Takuya Orita
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Tomoko Iwanaga
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Tsuyoshi Adachi
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Shingo Fujioka
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Tatsuo Akaki
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Kazutaka Ikegashira
- Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Yoshiji Hantani
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
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29
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Konovalov KA, Wu CG, Qiu Y, Balakrishnan VK, Parihar PS, O’Connor MS, Xing Y, Huang X. Disease mutations and phosphorylation alter the allosteric pathways involved in autoinhibition of protein phosphatase 2A. J Chem Phys 2023; 158:215101. [PMID: 37260014 PMCID: PMC10238128 DOI: 10.1063/5.0150272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/16/2023] [Indexed: 06/02/2023] Open
Abstract
Mutations in protein phosphatase 2A (PP2A) are connected to intellectual disability and cancer. It has been hypothesized that these mutations might disrupt the autoinhibition and phosphorylation-induced activation of PP2A. Since they are located far from both the active and substrate binding sites, it is unclear how they exert their effect. We performed allosteric pathway analysis based on molecular dynamics simulations and combined it with biochemical experiments to investigate the autoinhibition of PP2A. In the wild type (WT), the C-arm of the regulatory subunit B56δ obstructs the active and substrate binding sites exerting a dual autoinhibition effect. We find that the disease mutant, E198K, severely weakens the allosteric pathways that stabilize the C-arm in the WT. Instead, the strongest allosteric pathways in E198K take a different route that promotes exposure of the substrate binding site. To facilitate the allosteric pathway analysis, we introduce a path clustering algorithm for lumping pathways into channels. We reveal remarkable similarities between the allosteric channels of E198K and those in phosphorylation-activated WT, suggesting that the autoinhibition can be alleviated through a conserved mechanism. In contrast, we find that another disease mutant, E200K, which is in spatial proximity of E198, does not repartition the allosteric pathways leading to the substrate binding site; however, it may still induce exposure of the active site. This finding agrees with our biochemical data, allowing us to predict the activity of PP2A with the phosphorylated B56δ and provide insight into how disease mutations in spatial proximity alter the enzymatic activity in surprisingly different mechanisms.
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Affiliation(s)
- Kirill A. Konovalov
- Department of Chemistry, Theoretical Chemistry Institute, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | | | - Yunrui Qiu
- Department of Chemistry, Theoretical Chemistry Institute, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Vijaya Kumar Balakrishnan
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
| | - Pankaj Singh Parihar
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
| | - Michael S. O’Connor
- Biophysics Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Yongna Xing
- Authors to whom correspondence should be addressed: and
| | - Xuhui Huang
- Authors to whom correspondence should be addressed: and
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30
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Hong SH, Xi SY, Johns AC, Tang LC, Li A, Hum MN, Chartier CA, Jovanovic M, Shah NH. Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases. Chembiochem 2023; 24:e202200706. [PMID: 36893077 PMCID: PMC10192133 DOI: 10.1002/cbic.202200706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/05/2023] [Accepted: 03/09/2023] [Indexed: 03/10/2023]
Abstract
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.
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Affiliation(s)
- Suk ho Hong
- Department of Chemistry, Columbia University, New York, NY 10027
| | - Sarah Y. Xi
- Department of Chemistry, Columbia University, New York, NY 10027
| | - Andrew C. Johns
- Department of Chemistry, Columbia University, New York, NY 10027
| | - Lauren C. Tang
- Department of Biological Sciences, Columbia University, New York, NY 10027
| | - Allyson Li
- Department of Chemistry, Columbia University, New York, NY 10027
| | - Madeleine N. Hum
- Department of Chemistry, Columbia University, New York, NY 10027
| | | | - Marko Jovanovic
- Department of Biological Sciences, Columbia University, New York, NY 10027
| | - Neel H. Shah
- Department of Chemistry, Columbia University, New York, NY 10027
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Liu Y, Zhang J, Du Z, Huang J, Cheng Y, Yi W, Li T, Yang J, Chen C. Comprehensive analysis of PTPN family expression and prognosis in acute myeloid leukemia. Front Genet 2023; 13:1087938. [PMID: 36699453 PMCID: PMC9868563 DOI: 10.3389/fgene.2022.1087938] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Background: Tyrosyl phosphorylation is carried out by a group of enzymes known as non-receptor protein tyrosine phosphatases (PTPNs). In the current investigation, it is hoped to shed light on the relationships between the expression patterns of PTPN family members and the prognosis of acute myeloid leukemia (AML). Methods: PTPN expression was examined using GEPIA and GEO databases. To investigate the connection between PTPN expression and survival in AML patients, we downloaded data from the Broad TCGA Firehose and Clinical Proteomic Tumor Analysis (CPTAC) of the Cancer Genome Atlas (TCGA). We used quantitative real-time PCR (qRT-PCR) to confirm that essential genes were performed in clinical samples and cell lines. We then used western blot to verify that the genes expressed in the above databases were positive in normal tissues, AML patient samples, and AML cell lines. Next, we investigated associations between genome-wide expression profiles and PTPN6 expression using the GEO datasets. We investigated the interactive exploration of multidimensional cancer genomics using the cBioPortal datasets. Using the DAVID database, a study of gene ontology enrichment was performed. The protein-protein interaction (PPI) network was created using the STRING portal, and the gene-gene interaction network was performed using GeneMANIA. Results: Data from GEO and GEPIA revealed that most PTPN family members were linked to AML. Patients with leukemia have elevated levels of several PTPN members. All of the AML patients' poor overall survival (OS, p < .05) was significantly linked with higher expression of PTPN1, PTPN6, and PTPN7. Additionally, clinical samples showed that the expression of PTPN 6, PTPN 7, PTPN 13, and PTPN 14 was higher than normal in AML patients (p = .0116, p = .0034, p = .0092, and p = .0057, respectively) and AML cell lines (p = .0004, p = .0035, p = .0357, and p = .0177, respectively). Western blotting results showed that the expression of PTPN6 in AML samples and AML cell lines was significantly higher than that in normal control samples. Conclusion: Differentially expressed PTPN family members were found in AML. The prognosis of patients and PTPN gene expression were shown to be correlated. PTPN6 is one of these members and may be used as an AML diagnostic and prognostic marker.
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Affiliation(s)
- Yong Liu
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Jing Zhang
- Department of Breast and Thyroid Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Zefan Du
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Junbin Huang
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Yucai Cheng
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Wenfang Yi
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Tianwen Li
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Jing Yang
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Chun Chen
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
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32
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Feng B, Dong X, Liu Z, Zhang J, Liu H, Xu Y. Virtual Screening and Biological Evaluation of Novel Low Molecular Weight Protein Tyrosine Phosphatase Inhibitor for the Treatment of Insulin Resistance. Drug Des Devel Ther 2023; 17:1191-1201. [PMID: 37113468 PMCID: PMC10128076 DOI: 10.2147/dddt.s406956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Purpose Protein tyrosine phosphatases (PTPs) play an essential way in diseases including cancer, obesity, diabetes and autoimmune disorders. As a member of PTPs, low molecular weight PTP (LMPTP) has been a well-recognized anti-insulin resistance target in obesity. However, the number of reported LMPTP inhibitors is limited. Our research aims to discover a novel LMPTP inhibitor and evaluate its biological activity against insulin resistance. Methods A virtual screening pipeline based on the X-ray co-crystal complex of LMPTP was constructed. Enzyme inhibition assay and cellular bioassay were used to evaluate the activity of screened compounds. Results The screening pipeline rendered 15 potential hits from Specs chemical library. Enzyme inhibition assay identified compound F9 (AN-465/41163730) as a potential LMPTP inhibitor with a K i value of 21.5 ± 7.3 μM. Cellular bioassay showed F9 could effectively increase the glucose consumption of HepG2 cells as a result of releasing insulin resistance by regulating PI3K-Akt pathway. Conclusion In summary, this study presents a versatile virtual screening pipeline for potential LMPTP inhibitor discovery and provides a novel-scaffold lead compound that is worthy of further modification to get more potent LMPTP inhibitors.
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Affiliation(s)
- Bo Feng
- Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China
| | - Xu Dong
- Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China
| | - Zhen Liu
- Department of Neurology, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China
| | - Jie Zhang
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Hongyu Liu
- Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China
- Correspondence: Hongyu Liu; Yuan Xu, Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China, Email ;
| | - Yuan Xu
- Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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Cappabianca L, Sebastiano M, Ruggieri M, Sbaffone M, Zelli V, Farina AR, Mackay AR. Doxorubicin-Induced TrkAIII Activation: A Selection Mechanism for Resistant Dormant Neuroblastoma Cells. Int J Mol Sci 2022; 23:ijms231810895. [PMID: 36142807 PMCID: PMC9503591 DOI: 10.3390/ijms231810895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/06/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The acquisition of Dox resistance, however, is a major barrier to a sustained response and leads to a poor prognosis in advanced disease states, reinforcing the need to identify and inhibit Dox resistance mechanisms. In this context, we report on the identification and inhibition of a novel Dox resistance mechanism. This mechanism is characterized by the Dox-induced activation of the oncogenic TrkAIII alternative splice variant, resulting in increased Dox resistance, and is blocked by lestaurtinib, entrectinib, and crizotinib tyrosine kinase and LY294002 IP3-K inhibitors. Using time lapse live cell imaging, conventional and co-immunoprecipitation Western blots, RT-PCR, and inhibitor studies, we report that the Dox-induced TrkAIII activation correlates with proliferation inhibition and is CDK1- and Ca2+-uniporter-independent. It is mediated by ryanodine receptors; involves Ca2+-dependent interactions between TrkAIII, calmodulin and Hsp90; requires oxygen and oxidation; occurs within assembled ERGICs; and does not occur with fully spliced TrkA. The inhibitory effects of lestaurtinib, entrectinib, crizotinib, and LY294002 on the Dox-induced TrkAIII and Akt phosphorylation and resistance confirm roles for TrkAIII and IP3-K consistent with Dox-induced, TrkAIII-mediated pro-survival IP3K/Akt signaling. This mechanism has the potential to select resistant dormant TrkAIII-expressing NB cells, supporting the use of Trk inhibitors during Dox therapy in TrkAIII-expressing NBs.
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35
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Behl T, Gupta A, Sehgal A, Albarrati A, Albratty M, Meraya AM, Najmi A, Bhatia S, Bungau S. Exploring protein tyrosine phosphatases (PTP) and PTP-1B inhibitors in management of diabetes mellitus. Biomed Pharmacother 2022; 153:113405. [DOI: 10.1016/j.biopha.2022.113405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 11/02/2022] Open
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Differential mRNA Expression Profiling Reveals the Role of MiR-375 in Inflammation of Bovine Mammary Epithelial Cells. Animals (Basel) 2022; 12:ani12111431. [PMID: 35681895 PMCID: PMC9179474 DOI: 10.3390/ani12111431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Bovine mammary epithelial cells (bMECs) are often used as cell models for mammary gland research. They are the most important cells for mammary gland function and the first line of defense for pathogen identification. MicroRNAs (miRNAs) are important regulatory factors involved in many physiological and pathological processes. Here, we examined a transcriptome profile of bovine mammary epithelial cell lines transfected with miR-375 inhibitor or negative control (NC) inhibitor, and further reveal the potential role of miR-375 in bMECs by differentially expressed mRNA analysis. We found that miR-375 potentially promotes inflammation in the mammary gland through the MAPK signaling pathway. Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate post-transcriptional gene expression and several biological processes. Bovine mammary epithelial cells (bMECs) mediate critical immune responses in the mammary gland and the occurrence of mastitis. Current research focuses on miRNA regulation of bMECs, but the miR-375 regulatory mechanism in bMECs is unclear. This study explored the role of miR-375 by profiling the transcriptome of miR-375-silenced bMECs using RNA-seq and identifying differentially expressed mRNAs (DIE-mRNAs). There were 63 DIE-mRNAs, including 48 down-regulated and 15 up-regulated mRNAs between miR-375-silenced bMECs and the controls. The Kyoto encyclopedia of genes and genomes (KEGG) and Gene Ontology (GO) functional analysis showed that the DIE-mRNAs enriched nuclear receptor subfamily 4 group A member 1 (NR4A1) and protein tyrosine phosphatase non-receptor type 5 (PTPN5) anti-inflammatory genes of the mitogen-activated protein kinase (MAPK) signaling pathway. However, they showed an opposite trend to the expression of miR-375 silencing, suggesting that miR-375 promotes bMEC inflammation through the MAPK signaling pathway. The findings of this study provide a new reference for understanding the regulation of bMEC inflammation and cow mastitis.
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Kuang W, Wang X, Ding J, Li J, Ji M, Chen W, Wang L, Yang P. PTPN2, A Key Predictor of Prognosis for Pancreatic Adenocarcinoma, Significantly Regulates Cell Cycles, Apoptosis, and Metastasis. Front Immunol 2022; 13:805311. [PMID: 35154122 PMCID: PMC8829144 DOI: 10.3389/fimmu.2022.805311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
Objective This study conducted a comprehensive analysis of the members of the PTPN family and emphasized the key role of PTPN2 as a potential therapeutic target and diagnostic biomarker in improving the survival rate of PAAD. Method Oncomine was used to analyze the pan-cancer expression of the PTPN gene family. The Cancer Genome Atlas (TCGA) data as well as Genotype-Tissue Expression (GTEx) data were downloaded to analyze the expression and prognosis of PTPNs. The diagnosis of PTPNs was evaluated by the experimental ROC curve. The protein-protein interaction (PPI) network was constructed by combining STRING and Cytoscape. The genes of 50 proteins most closely related to PTPN2 were screened and analyzed by GO and KEGG enrichment. The differentially expressed genes of PTPN2 were found by RNA sequencing, and GSEA enrichment analysis was carried out to find the downstream pathways and targets, which were verified by online tools and experiments. Finally, the relationship between PTPN2 and immune cell infiltration in PAAD, and the relationship with immune score and immune checkpoint were studied. Result The expression patterns and the prognostic value of multiple PTPNs in PAAD have been reported through bioinformatic analyzes. Among these members, PTPN2 is the most important prognostic signature that regulates the progression of PAAD by activating JAK-STAT signaling pathway. Comparison of two PAAD cell lines with normal pancreatic epithelial cell lines revealed that PTPN2 expression was up-regulated as a key regulator of PAAD, which was associated with poor prognosis. Knockdown of PTPN2 caused a profound decrease in PAAD cell growth, migration, invasion, and induced PAAD cell cycle and apoptosis. In addition, we conducted a series of enrichment analyses to investigate the PTPN2-binding proteins and the PTPN2 expression-correlated genes. We suggest that STAT1 and EGFR are the key factors to regulate PTPN2, which are involved in the progression of PAAD. Meanwhile, the silencing of PTPN2 induced the repression of STAT1 and EGFR expression. Conclusion These findings provide a comprehensive analysis of the PTPN family members, and for PAAD, they also demonstrate that PTPN2 is a diagnostic biomarker and a therapeutic target.
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Affiliation(s)
- Wenbin Kuang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiao Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiayu Ding
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiaxing Li
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Minghui Ji
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Weijiao Chen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liping Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
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Hou X, Du J, Fang H. PTPRO is a therapeutic target and correlated with immune infiltrates in pancreatic cancer. J Cancer 2022; 12:7445-7453. [PMID: 35003364 PMCID: PMC8734421 DOI: 10.7150/jca.64661] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 10/04/2021] [Indexed: 11/17/2022] Open
Abstract
As a member of protein tyrosine phosphatases (PTPs), the protein tyrosine phosphatase receptor type O (PTPRO) has attracted increasing attention for its important roles in cell signaling. Currently, the roles of PTPRO in human cancers remain elusive. Herein, we performed bioinformatic analyses and revealed the potential oncogenic role of PTPRO in specific cancer types. Further in vitro experiments indicated that inhibition of PTPRO suppresses the proliferative abilities of tumor cells in pancreatic cancer, blood cancer, and breast cancer. Moreover, small molecular PTPRO inhibitor could induce cell apoptosis and affect the cell cycle in pancreatic cancer. In addition, PTPRO expression promoted the infiltration of CD8+ T, macrophages, dendritic cells, and neutrophils, in pancreatic cancers. Our findings suggested PTPRO may serve as a potential drug target for pancreatic cancer.
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Affiliation(s)
- Xuben Hou
- Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
| | - Jintong Du
- Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, Shandong, 250117, China
| | - Hao Fang
- Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China
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Chauhan P, Mundekkad D, Mukherjee A, Chaudhary S, Umar A, Baskoutas S. Coconut Carbon Dots: Progressive Large-Scale Synthesis, Detailed Biological Activities and Smart Sensing Aptitudes towards Tyrosine. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:162. [PMID: 35010113 PMCID: PMC8746512 DOI: 10.3390/nano12010162] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 02/04/2023]
Abstract
In the recent era, carbon dots (C-dots) have been extensively considered as a potential tool in drug delivery analysis. However, there have been fewer reports in the literature on their application in the sensing of amino acids. As part of our ongoing research on coconut-husk-derived C-dots, we synthesized C-dots under different temperature conditions and utilized them in the field of amino acid sensing and found them to be highly selective and sensitive towards tyrosine. The detailed characterization of the prepared C-dots was carried out. The developed C-dots exhibit good values of quantum yield. BSA, HSA and glutamic acid were utilized to explore the binding efficiency of C-dots with biologically active components. Hemolysis, blood clotting index activity and cell viability assays using the prepared C-dots were evaluated and they were found to be biocompatible. Therefore, the C-dots described in this work have high potential to be utilized in the field of amino acid sensing, especially L-tyrosine. The limit of detection and the binding constant for the developed C-dots in the presence of tyrosine were found to be 0.96 nM and 296.38 nM-1, respectively. The efficiency of the developed C-dots was also investigated in the presence of various other amino acids and different water mediums in order to enhance the working scope of the developed sensors.
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Affiliation(s)
- Pooja Chauhan
- Centre of Advanced Studies in Chemistry, Department of Chemistry, Panjab University, Chandigarh 160014, India;
| | - Deepa Mundekkad
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore 632014, India; (D.M.); (A.M.)
| | - Amitava Mukherjee
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore 632014, India; (D.M.); (A.M.)
| | - Savita Chaudhary
- Centre of Advanced Studies in Chemistry, Department of Chemistry, Panjab University, Chandigarh 160014, India;
| | - Ahmad Umar
- Department of Chemistry, College of Science and Arts, Najran University, Najran 11001, Saudi Arabia
- Promising Centre for Sensors and Electronic Devices (PCSED), Najran University, Najran 11001, Saudi Arabia
| | - Sotirios Baskoutas
- Department of Materials Science, University of Patras, 265 04 Patras, Greece
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40
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Henderson IM, Zeng F, Bhuiyan NH, Luo D, Martinez M, Smoake J, Bi F, Perera C, Johnson D, Prisinzano TE, Wang W, Uhl GR. Structure-activity studies of PTPRD phosphatase inhibitors identify a 7-cyclopentymethoxy illudalic acid analog candidate for development. Biochem Pharmacol 2022; 195:114868. [PMID: 34863978 PMCID: PMC9248268 DOI: 10.1016/j.bcp.2021.114868] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 12/30/2022]
Abstract
Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRD's phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA. Several were more selective for PTPRD vs the receptor type protein tyrosine phosphatases S, F and J or the nonreceptor type protein tyrosine phosphatase N1 (PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B), phosphatases at which 7-BIA displays activity. In silico studies aided design of novel analogs. A 7-position cyclopentyl methoxy substituted 7-BIA analog termed NHB1109 displayed 600-700 nM potencies in inhibiting PTPRD and PTPRS, improved selectivity vs PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B phosphatases, no substantial potency at other protein tyrosine phosphatases screened, no significant potency at any of the targets of clinically-useful drugs identified in EUROFINS screens and significant oral bioavailability. Oral doses up to 200 mg/kg were well tolerated by mice, though higher doses resulted in reduced weight and apparent ileus without clear organ histopathology. NHB1109 provides a good candidate to advance to in vivo studies in addiction paradigms and toward human use to reduce reward from addictive substances.
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Affiliation(s)
- Ian M Henderson
- Biomedical Research Institute of New Mexico, Albuquerque, NM, United States; New Mexico VA Healthcare System, Albuquerque, NM, United States
| | - Fanxun Zeng
- College of Pharmacy, University of Arizona, Tucson, AZ, United States
| | - Nazmul H Bhuiyan
- College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Dan Luo
- College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Maria Martinez
- Biomedical Research Institute of New Mexico, Albuquerque, NM, United States; New Mexico VA Healthcare System, Albuquerque, NM, United States
| | - Jane Smoake
- Biomedical Research Institute of New Mexico, Albuquerque, NM, United States; New Mexico VA Healthcare System, Albuquerque, NM, United States
| | - Fangchao Bi
- College of Pharmacy, University of Arizona, Tucson, AZ, United States
| | | | | | | | - Wei Wang
- College of Pharmacy, University of Arizona, Tucson, AZ, United States.
| | - George R Uhl
- Biomedical Research Institute of New Mexico, Albuquerque, NM, United States; New Mexico VA Healthcare System, Albuquerque, NM, United States; Departments of Neurology, Neuroscience and Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, United States; Departments of Neurology and Pharmacology, University of Maryland School of Medicine, Baltimore, MD, United States; VA Maryland Healthcare System, Baltimore, MD, United States.
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41
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Qin X, Liu T. Recent Advances in Genetic Code Expansion Techniques for Protein Phosphorylation Studies. J Mol Biol 2021; 434:167406. [PMID: 34929199 DOI: 10.1016/j.jmb.2021.167406] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 12/03/2021] [Accepted: 12/10/2021] [Indexed: 12/22/2022]
Abstract
Protein phosphorylation is a reversible, residue-specific posttranslational modification that plays a pivotal role in cell signaling, and the phosphorylation state of proteins is tightly regulated by kinases and phosphatases. Malfunction of this regulation is often associated with human diseases, and therefore elucidation of the function and regulation of this posttranslational modification is important. Genetic code expansion, which allows for site-specific introduction of noncanonical amino acids directly into target proteins in response to a non-sense codon is a powerful method for preparing homogeneously phosphorylated proteins both in Escherichia coli and mammalian cells and therefore is useful for studying protein phosphorylation. Herein, we summarize recent developments in the application of genetic code expansion for protein phosphorylation studies.
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Affiliation(s)
- Xuewen Qin
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Tao Liu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
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42
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Ren YM, Zhang R, Feng Z, Ke CQ, Yao S, Tang C, Lin L, Ye Y. Macrocephatriolides A and B: Two Guaianolide Trimers from Ainsliaea macrocephala as PTP1B Inhibitors and Insulin Sensitizers. J Org Chem 2021; 86:17782-17789. [PMID: 34851120 DOI: 10.1021/acs.joc.1c01996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Macrocephatriolides A and B (1 and 2), two novel guaiane-type sesquiterpene lactone trimers possessing unique linkage patterns, were identified from the whole plant of Ainsliaea macrocephala. The trimeric architecture of 1 features a cyclohexene linkage and a methylene bridge, which were presumably constructed from three constitutive monomers via a Diels-Alder cycloaddition and a Michael addition, respectively. The three monomers of 2 were tethered by a 1,2-ethanediyl and a methylene linkage at the same time. Their complex structures were established by extensive analysis of spectroscopic data inclusive of band-selective CT-HSQC and CT-HMBC and time-dependent density functional theory (TDDFT) ECD calculations. Compound 2 showed potent inhibition against protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 26.26 ± 0.88 μM but not compound 1. In the kinetic study, compound 2 was disclosed as a competitive inhibitor of PTP1B with a Ki value of 16.34 ± 4.72 μM. In insulin-stimulated C2C12 myotubes, compound 2 dose-dependently enhanced glucose uptake by activating the insulin signaling pathway. Compound 2 might represent a new scaffold of insulin sensitizers.
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Affiliation(s)
- Yong-Mei Ren
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.,University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.,School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, People's Republic of China
| | - Rui Zhang
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China
| | - Zheling Feng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Chang-Qiang Ke
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China
| | - Sheng Yao
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China
| | - Chunping Tang
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Yang Ye
- State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.,University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.,School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, People's Republic of China
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43
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Xie F, Dong H, Zhang H. Regulatory Functions of Protein Tyrosine Phosphatase Receptor Type O in Immune Cells. Front Immunol 2021; 12:783370. [PMID: 34880876 PMCID: PMC8645932 DOI: 10.3389/fimmu.2021.783370] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 11/04/2021] [Indexed: 01/01/2023] Open
Abstract
The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.
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Affiliation(s)
- Feiling Xie
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Hongmei Dong
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Hao Zhang
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China
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44
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Elhassan RM, Hou X, Fang H. Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery. Med Res Rev 2021; 42:1064-1110. [PMID: 34791703 DOI: 10.1002/med.21871] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 09/26/2021] [Accepted: 10/24/2021] [Indexed: 01/07/2023]
Abstract
Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable target-selectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular mechanistic studies illustrating applications in chemical biology and medicinal chemistry.
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Affiliation(s)
- Reham M Elhassan
- Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China
| | - Xuben Hou
- Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China
| | - Hao Fang
- Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China
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45
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Yang Y, Zhang L, Tian J, Ye F, Xiao Z. Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site. J Chem Inf Model 2021; 61:4720-4732. [PMID: 34521197 DOI: 10.1021/acs.jcim.1c00357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is an intractable target for drug discovery due to its conservative and cationic catalytic site. Targeting alternative allosteric sites of PTP1B is a promising strategy to achieve specificity and bioavailability. A hierarchical virtual screening based on a previously identified allosteric site was applied to search for potential PTP1B inhibitors with better pharmacological profiles. Four potent PTP1B inhibitors (H1, H3, H7, and H9) with structures distinct from known inhibitors were identified. Among them, H3 and H9 demonstrated evident selectivity to PTP1B over homologous T-cell protein tyrosine phosphatase (TCPTP) and SHP2. Molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) calculations recognized Phe280, Phe196, Leu192, and Asn193 as key residues responsible for potent allosteric inhibition and excellent PTP selectivity. The results not only expand the structural diversity but also aid the future molecular design of PTP1B allosteric inhibitors.
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Affiliation(s)
- Ying Yang
- Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China
| | - Lei Zhang
- Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China
| | - Jinying Tian
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China
| | - Fei Ye
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China
| | - Zhiyan Xiao
- Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China
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46
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Functional interrogation and therapeutic targeting of protein tyrosine phosphatases. Biochem Soc Trans 2021; 49:1723-1734. [PMID: 34431504 DOI: 10.1042/bst20201308] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/28/2021] [Accepted: 07/30/2021] [Indexed: 12/17/2022]
Abstract
Protein tyrosine phosphatases (PTPs) counteract the enzymatic activity of protein tyrosine kinases to modulate levels of both normal and disease-associated protein tyrosine phosphorylation. Aberrant activity of PTPs has been linked to the progression of many disease states, yet no PTP inhibitors are currently clinically available. PTPs are without a doubt a difficult drug target. Despite this, many selective, potent, and bioavailable PTP inhibitors have been described, suggesting PTPs should once again be looked at as viable therapeutic targets. Herein, we summarize recently discovered PTP inhibitors and their use in the functional interrogation of PTPs in disease states. In addition, an overview of the therapeutic targeting of PTPs is described using SHP2 as a representative target.
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47
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Su H, Jiang M, Senevirathne C, Aluri S, Zhang T, Guo H, Xavier-Ferrucio J, Jin S, Tran NT, Liu SM, Sun CW, Zhu Y, Zhao Q, Chen Y, Cable L, Shen Y, Liu J, Qu CK, Han X, Klug CA, Bhatia R, Chen Y, Nimer SD, Zheng YG, Iancu-Rubin C, Jin J, Deng H, Krause DS, Xiang J, Verma A, Luo M, Zhao X. Methylation of dual-specificity phosphatase 4 controls cell differentiation. Cell Rep 2021; 36:109421. [PMID: 34320342 PMCID: PMC9110119 DOI: 10.1016/j.celrep.2021.109421] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/17/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.
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Affiliation(s)
- Hairui Su
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ming Jiang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Chamara Senevirathne
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Srinivas Aluri
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA
| | - Tuo Zhang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Han Guo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Juliana Xavier-Ferrucio
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Shuiling Jin
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ngoc-Tung Tran
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Szu-Mam Liu
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Chiao-Wang Sun
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yongxia Zhu
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Qing Zhao
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yuling Chen
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
| | | | - Yudao Shen
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jing Liu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Cheng-Kui Qu
- Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Xiaosi Han
- Department of Neurology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Christopher A Klug
- Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ravi Bhatia
- Division of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yabing Chen
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Veterans Affairs Birmingham Medical Center, Research Department, Birmingham, AL 35294, USA
| | - Stephen D Nimer
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33146 USA
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Camelia Iancu-Rubin
- Department of Medicine, Hematology and Oncology Division, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Haiteng Deng
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Diane S Krause
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jenny Xiang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Amit Verma
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
| | - Minkui Luo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA.
| | - Xinyang Zhao
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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48
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Zhang Q, Fan Z, Zhang L, You Q, Wang L. Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer. J Med Chem 2021; 64:8916-8938. [PMID: 34156850 DOI: 10.1021/acs.jmedchem.1c00631] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Among numerous posttranslational regulation patterns, phosphorylation is reversibly controlled by the balance of kinases and phosphatases. The major form of cellular signaling involves the reversible phosphorylation of proteins on tyrosine, serine, or threonine residues. However, altered phosphorylation levels are found in diverse diseases, including cancer, making kinases and phosphatases ideal drug targets. In contrast to the success of prosperous kinase inhibitors, design of small molecules targeting phosphatase is struggling due to past bias and difficulty. This is especially true for serine/threonine phosphatases, one of the largest phosphatase families. From this perspective, we aim to provide insights into serine/threonine phosphatases and the small molecules targeting these proteins for drug development, especially in cancer. Through highlighting the modulation strategies, we aim to provide basic principles for the design of small molecules and future perspectives for the application of drugs targeting serine/threonine phosphatases.
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Affiliation(s)
- Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhongjiao Fan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lianshan Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai 200245, China
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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49
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Guo Y, Xu Y, Dong X, Zhang J. Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors. ChemistrySelect 2021. [DOI: 10.1002/slct.202100186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yu Guo
- Hangzhou Institute of Innovative Medicine College of Pharmaceutical Sciences Zhejiang University Hangzhou 310058 P.R. China
| | - Yaping Xu
- Hangzhou Institute of Innovative Medicine College of Pharmaceutical Sciences Zhejiang University Hangzhou 310058 P.R. China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine College of Pharmaceutical Sciences Zhejiang University Hangzhou 310058 P.R. China
| | - Jianjun Zhang
- Department of Pharmacy Institution The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine) Hangzhou 310006 P.R. China
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50
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Wang Y, Yang L, Wang M, Zhang J, Qi W, Su R, He Z. Bioinspired Phosphatase-like Mimic Built from the Self-Assembly of De Novo Designed Helical Short Peptides. ACS Catal 2021. [DOI: 10.1021/acscatal.1c00129] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Yutong Wang
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
| | - Lijun Yang
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
| | - Mengfan Wang
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
- Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin 300350, P. R. China
| | - Jiaxing Zhang
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
| | - Wei Qi
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
- The Co-Innovation Centre of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, P. R. China
- Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin 300350, P. R. China
| | - Rongxin Su
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
- The Co-Innovation Centre of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, P. R. China
- Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin 300350, P. R. China
| | - Zhimin He
- School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300350, P. R. China
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