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Lu J, Yu D, Li H, Qin P, Chen H, Chen L. Promising natural products targeting protein tyrosine phosphatase SHP2 for cancer therapy. Phytother Res 2025; 39:1735-1757. [PMID: 38558278 DOI: 10.1002/ptr.8185] [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: 09/01/2023] [Revised: 02/27/2024] [Accepted: 02/29/2024] [Indexed: 04/04/2024]
Abstract
The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microenvironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate different cancers and thus pave the way for further development of anticancer drugs targeting SHP2.
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Affiliation(s)
- Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Danmei Yu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongtao Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Pengcheng Qin
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Pharmacy, Henan University, Kaifeng, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Manjunath GK, Ankam KV, Dakal TC, Srihari Sharma MV, Nashier D, Mitra T, Kumar A. Unraveling the genetic and singaling landscapes of pediatric cancer. Pathol Res Pract 2024; 263:155635. [PMID: 39393268 DOI: 10.1016/j.prp.2024.155635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/18/2024] [Accepted: 10/02/2024] [Indexed: 10/13/2024]
Abstract
Pediatric cancer (PAEC) arises from gene mutations and their disrupted pathways, often driven by genetic instability affecting cell signaling. These pathways can help identify cancer triggers. Genomic studies have examined PAEC gene etiologies and disorders, but further analysis is needed to understand tumor progression mechanisms. We systematically analyzed PAEC datasets from cBioPortal, encompassing thirteen studies with 6568 samples. We identified 827 PAEC genes with mutation frequencies over fifteen across four tiers (I-IV). Tier I (mutation frequency ≥1 %) includes 40 genes, while Tier II(0.90-0.70 %), Tier III(0.60-0.50 %), and Tier IV(0.40-0.10 %) comprise 126, 336, and 325 genes, respectively. Key Tier I genes include TP53(5 %), NRAS(2.2 %), KRAS(1.8 %), CTNNB1(1.4 %), ATM(1.3 %), CREBBP(1.2 %), JAK2 (1.1 %), PIK3CA(1 %), PTEN(1 %), BRAF(0.9 %), EGFR(0.9 %), PIK3R1(0.8 %), and PTPN11(0.8 %). These genes participate in various signaling pathways (PI3K/AKT/mTOR, RAS/RAF/MAPK, JAK/STAT, and WNT/β-catenin), which are interconnected. We compared several PAEC panels with Tier I genes, and we found that the most shared across PAEC panels were TP53 (8), PTEN (7), and ATM (4). We further examined roles of TP53 in normal cells versus PEAC tumors using digital cellular and pathological imaging data supported by Human Protein Atlas. TP53 is expressed in cytosol, nucleosol, and vesicles and during cell-cycle TP53 protein in key regulator and it is present during all major cell-cycle events. Balancing of TP53WT and TP53MUT is the hallmark of the TP53 pathophysiology with severe functional implications. Notably, genes linked to insulin metabolism disorders may be PAEC risk factors, suggesting metabolic pathways as key research targets. This study highlights the therapeutic, prognostic, and diagnostic significance of these genes and pathways, emphasizing the need for ongoing PAEC research.
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Affiliation(s)
- Gowrang Kasaba Manjunath
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India
| | - Krishna Veni Ankam
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India
| | - Tikam Chand Dakal
- Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia, University, Udaipur, Rajasthan 313001, India
| | - M V Srihari Sharma
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India
| | - Disha Nashier
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India
| | - Tamoghna Mitra
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India
| | - Abhishek Kumar
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India; Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore, Karnataka 560066, India.
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Li HY, Jing YM, Shen X, Tang MY, Shen HH, Li XW, Wang ZS, Su F. Protein tyrosine phosphatase non-receptor II: A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:3913-3931. [PMID: 39350977 PMCID: PMC11438766 DOI: 10.4251/wjgo.v16.i9.3913] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/03/2024] [Accepted: 07/08/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND The incidence of primary liver cancer is increasing year by year. In 2022 alone, more than 900000 people were diagnosed with liver cancer worldwide, with hepatocellular carcinoma (HCC) accounting for 75%-85% of cases. HCC is the most common primary liver cancer. China has the highest incidence and mortality rate of HCC in the world, and it is one of the malignant tumors that seriously threaten the health of Chinese people. The onset of liver cancer is occult, the early cases lack typical clinical symptoms, and most of the patients are already in the middle and late stage when diagnosed. Therefore, it is very important to find new markers for the early detection and diagnosis of liver cancer, improve the therapeutic effect, and improve the prognosis of patients. Protein tyrosine phosphatase non-receptor 2 (PTPN2) has been shown to be associated with colorectal cancer, triple-negative breast cancer, non-small cell lung cancer, and prostate cancer, but its biological role and function in tumors remain to be further studied. AIM To combine the results of relevant data obtained from The Cancer Genome Atlas (TCGA) to provide the first in-depth analysis of the biological role of PTPN2 in HCC. METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database, and the findings were then verified by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting. The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features. Finally, the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining. RESULTS The results of immunohistochemical staining, qRT-PCR, and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways, including cancer-related pathways, the Notch signaling pathway, and the MAPK signaling pathway. Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways, such as the epithelial mesenchymal transition process. A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group. CONCLUSION This study investigated PTPN2 from multiple biological perspectives, revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
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Affiliation(s)
- Hui-Yuan Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Yi-Ming Jing
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xue Shen
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Ming-Yue Tang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Hong-Hong Shen
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xin-Wei Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Zi-Shu Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Fang Su
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
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Bennett GM, Starczewski J, dela Cerna MVC. In silico identification of putative druggable pockets in PRL3, a significant oncology target. Biochem Biophys Rep 2024; 39:101767. [PMID: 39050014 PMCID: PMC11267023 DOI: 10.1016/j.bbrep.2024.101767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Protein tyrosine phosphatases (PTP) have emerged as targets in diseases characterized by aberrant phosphorylations such as cancers. The activity of the phosphatase of regenerating liver 3, PRL3, has been linked to several oncogenic and metastatic pathways, particularly in breast, ovarian, colorectal, and blood cancers. Development of small molecules that directly target PRL3, however, has been challenging. This is partly due to the lack of structural information on how PRL3 interacts with its inhibitors. Here, computational methods are used to bridge this gap by evaluating the druggability of PRL3. In particular, web-based pocket prediction tools, DoGSite3 and FTMap, were used to identify binding pockets using structures of PRL3 currently available in the Protein Data Bank. Druggability assessment by molecular dynamics simulations with probes was also performed to validate these results and to predict the strength of binding in the identified pockets. While several druggable pockets were identified, those in the closed conformation show more promise given their volume and depth. These two pockets flank the active site loops and roughly correspond to pockets predicted by molecular docking in previous papers. Notably, druggability simulations predict the possibility of low nanomolar affinity inhibitors in these sites implying the potential to identify highly potent small molecule inhibitors for PRL3. Putative pockets identified here can be leveraged for high-throughput virtual screening to further accelerate the drug discovery against PRL3 and development of PRL3-directed therapeutics.
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Affiliation(s)
- Grace M. Bennett
- Department of Biochemistry, Chemistry, and Physics, Georgia Southern University, Savannah, GA, 31419, USA
| | - Julia Starczewski
- Department of Biochemistry, Chemistry, and Physics, Georgia Southern University, Savannah, GA, 31419, USA
| | - Mark Vincent C. dela Cerna
- Department of Biochemistry, Chemistry, and Physics, Georgia Southern University, Savannah, GA, 31419, USA
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Zhao Y, Cui Y, Ni W, Yu S, Pan D, Liu S, Jia Z, Gao Y, Zhao D, Liu M, Wang S. Ginseng total saponin improves red blood cell oxidative stress injury by regulating tyrosine phosphorylation and glycolysis in red blood cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155785. [PMID: 38823342 DOI: 10.1016/j.phymed.2024.155785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/17/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND Oxidative stress is the main cause of many diseases, but because of its complex pathogenic factors, there is no clear method for treating it. Ginseng total saponin (GTS) an important active ingredients in Panax ginseng C.A. Mey (PG) and has potential therapeutic ability for oxidative stress due to various causes. However, the molecular mechanism of GTS in the treating oxidative stress damage in red blood cells (RBCs) is still unclear. PURPOSE This study aimed to examine the protective effect of GTS on RBCs under oxidative stress damage and to determine its potential mechanism. METHODS The oxidative stress models of rat RBCs induced by hydrogen peroxide (H2O2) and exhaustive swimming in vivo and in vitro was used. We determined the cell morphology, oxygen carrying capacity, apoptosis, antioxidant capacity, and energy metabolism of RBCs. The effect of tyrosine phosphorylation (pTyr) of Band 3 protein on RBCs glycolysis was also examined. RESULTS GTS reduced the hemolysis of RBCs induced by H2O2 at the lowest concentration. Moreover, GTS effectively improved the morphology, enhanced the oxygen carrying capacity, and increased antioxidant enzyme activity, adenosine triphosphate (ATP) levels, and adenosine triphosphatase (ATPase) activity in RBCs. GTS also promoted the expression of membrane proteins in RBCs, inhibited pTyr of Band 3 protein, and further improved glycolysis, restoring the morphological structure and physiological function of RBCs. CONCLUSIONS This study shows, that GTS can protect RBCs from oxidative stress damage by improving RBCs morphology and physiological function. Changes in pTyr expression and its related pTyr regulatory enzymes before and after GTS treatment suggest that Band 3 protein is the main target of GTS in the treating endogenous and exogenous oxidative stress. Moreover, GTS can enhance the glycolytic ability of RBCs by inhibiting pTyr of Band 3 protein, thereby restoring the function of RBCs.
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Affiliation(s)
- Yuchu Zhao
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Yuan Cui
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Weifeng Ni
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Shiting Yu
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Daian Pan
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Shichao Liu
- Academic Affairs Office, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Ziyi Jia
- School of Pharmacy, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Yanan Gao
- School of Pharmacy, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Daqing Zhao
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China
| | - Meichen Liu
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China.
| | - Siming Wang
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, China.
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Welsh CL, Allen S, Madan LK. Setting sail: Maneuvering SHP2 activity and its effects in cancer. Adv Cancer Res 2023; 160:17-60. [PMID: 37704288 PMCID: PMC10500121 DOI: 10.1016/bs.acr.2023.03.003] [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] [Indexed: 09/15/2023]
Abstract
Since the discovery of tyrosine phosphorylation being a critical modulator of cancer signaling, proteins regulating phosphotyrosine levels in cells have fast become targets of therapeutic intervention. The nonreceptor protein tyrosine phosphatase (PTP) coded by the PTPN11 gene "SHP2" integrates phosphotyrosine signaling from growth factor receptors into the RAS/RAF/ERK pathway and is centrally positioned in processes regulating cell development and oncogenic transformation. Dysregulation of SHP2 expression or activity is linked to tumorigenesis and developmental defects. Even as a compelling anti-cancer target, SHP2 was considered "undruggable" for a long time owing to its conserved catalytic PTP domain that evaded drug development. Recently, SHP2 has risen from the "undruggable curse" with the discovery of small molecules that manipulate its intrinsic allostery for effective inhibition. SHP2's unique domain arrangement and conformation(s) allow for a truly novel paradigm of inhibitor development relying on skillful targeting of noncatalytic sites on proteins. In this review we summarize the biological functions, signaling properties, structural attributes, allostery and inhibitors of SHP2.
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Affiliation(s)
- Colin L Welsh
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Sarah Allen
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, United States
| | - Lalima K Madan
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
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Zhu W, Luo N, Li Q, Chen X, Li X, Fu M, Yang F, Chen Z, Zhang Y, Zhang Y, Peng X, Hu G. Development and validation of an inflammatory response-related prognostic model and immune infiltration analysis in glioblastoma. ANNALS OF TRANSLATIONAL MEDICINE 2023; 11:69. [PMID: 36819551 PMCID: PMC9929762 DOI: 10.21037/atm-22-6271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
Background Despite receiving standard treatment, the prognosis of glioblastoma (GBM) patients is still poor. Considering the heterogeneity of each patient, it is imperative to identify reliable risk model that can effectively predict the prognosis of each GBM patient to guide the personalized treatment. Methods Transcriptomic gene expression profiles and corresponding clinical data of GBM patients were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Inflammatory response-related genes were extracted from Gene Set Enrichment Analysis (GSEA) website. Univariate Cox regression analysis was used for prognosis-related inflammatory genes (P<0.05). A polygenic prognostic risk model was constructed using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Validation was performed through CGGA cohort. Overall survival (OS) was compared by Kaplan-Meier analysis. A nomogram was plotted to accurately predict the prognosis for each patient. GSEA was used for the pathway enrichment analysis. The single sample GSEA (ssGSEA) algorithm was implemented to conduct the immune infiltration analysis. The potential role of oncostatin M receptor (OSMR) in GBM was investigated through the in vitro experiment. Results A prognostic risk model consisting of 4 genes (PTPRN, OSMR, MYD88, and EFEMP2) was developed. GBM patients in the high-risk group had worse OS. The time-dependent ROC curves showed an area under the curve (AUC) of 0.782, 0.765, and 0.784 for 1-, 2-, and 3-year survival in TCGA cohort, while the AUC in the CGGA cohort was 0.589, 0.684, and 0.785 at 1, 2, and 3 years, respectively. The risk score, primary-recurrent-secondary (PRS) type, and isocitrate dehydrogenase (IDH) mutation could predict the prognosis of GBM patients well. The nomogram accurately predicted the 1-, 2-, and 3-year OS for each patient. Immune cell infiltration was associated with the risk score and the model could predict immunotherapy responsiveness. The expression of the prognostic gene was correlated with the sensitivity to antitumor drugs. Interference of OSMR inhibited proliferation and migration and promoted apoptosis of GBM cells. Conclusions The prognostic model based on 4 inflammatory response-related genes had reliable predictive power to effectively predict clinical outcome in GBM patients and provided the guide for the personalized treatment.
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Affiliation(s)
- Wenjun Zhu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Luo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianxia Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Fu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziqi Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiling Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanyuan Zhang
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohong Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangyuan Hu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ali MK, Tian X, Zhao L, Schimmel K, Rhodes CJ, Wilkins MR, Nicolls MR, Spiekerkoetter EF. PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension. Cells 2023; 12:316. [PMID: 36672250 PMCID: PMC9857213 DOI: 10.3390/cells12020316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023] Open
Abstract
Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.
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Affiliation(s)
- Md Khadem Ali
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
| | - Xuefei Tian
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
| | - Lan Zhao
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
| | - Katharina Schimmel
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christopher J. Rhodes
- National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London W12 0NN, UK
| | - Martin R. Wilkins
- National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London W12 0NN, UK
| | - Mark R. Nicolls
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
| | - Edda F. Spiekerkoetter
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA
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Vasamsetti BMK, Kim YJ, Kang JH, Choi JW. Analysis of Phosphatase Activity in a Droplet-Based Microfluidic Chip. BIOSENSORS 2022; 12:bios12090740. [PMID: 36140125 PMCID: PMC9496282 DOI: 10.3390/bios12090740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/22/2022] [Accepted: 09/05/2022] [Indexed: 11/27/2022]
Abstract
We report analysis of phosphatase activity and inhibition on droplet-based microfluidic chips. Phosphatases are such attractive potential drug targets because abnormal phosphatase activity has been implicated in a variety of diseases including cancer, neurological disorders, diabetes, osteoporosis, and obesity. So far, several methods for assessing phosphatase activity have been reported. However, they require a large sample volume and additional chemical modifications such as fluorescent dye conjugation and nanomaterial conjugation, and are not cost-effective. In this study, we used an artificial phosphatase substrate 3-O-methylfluorescein phosphate as a fluorescent reporter and dual specificity phosphatase 22. Using these materials, the phosphatase assay was performed from approximately 340.4 picoliter (pL) droplets generated at a frequency of ~40 hertz (Hz) in a droplet-based microfluidic chip. To evaluate the suitability of droplet-based platform for screening phosphatase inhibitors, a dose–response inhibition study was performed with ethyl-3,4-dephostatin and the half-maximal inhibitory concentration (IC50) was calculated as 5.79 ± 1.09 μM. The droplet-based results were compared to microplate-based experiments, which showed agreement. The droplet-based phosphatase assay proposed here is simple, reproducible, and generates enormous data sets within the limited sample and reagent volumes.
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Affiliation(s)
- Bala Murali Krishna Vasamsetti
- Department of Biomedical Science, Cheongju University, Cheongju 28160, Korea
- Toxicity and Risk Assessment Division, Department of Agro-Food Safety and Crop Protection, National Institute of Agricultural Sciences, Rural Development Administration, Wanju-gun 55365, Korea
| | - Yeon-Jun Kim
- Department of Biomedical Science, Cheongju University, Cheongju 28160, Korea
| | - Jung Hoon Kang
- Department of Biomedical Science, Cheongju University, Cheongju 28160, Korea
| | - Jae-Won Choi
- Department of Biomedical Science, Cheongju University, Cheongju 28160, Korea
- Department of Bioindustrial Engineering, Cheongju University, Cheongju 28503, Korea
- Correspondence: or ; Tel.: +82-43-229-8528
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Song J, Lan J, Tang J, Luo N. PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. Int J Mol Sci 2022; 23:ijms231710025. [PMID: 36077422 PMCID: PMC9456094 DOI: 10.3390/ijms231710025] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers’ attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.
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11
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Buck SJ, Plaman BA, Bishop AC. Inhibition of SHP2 and SHP1 Protein Tyrosine Phosphatase Activity by Chemically Induced Dimerization. ACS OMEGA 2022; 7:14180-14188. [PMID: 35559188 PMCID: PMC9089384 DOI: 10.1021/acsomega.2c00780] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/21/2022] [Indexed: 06/15/2023]
Abstract
Protein tyrosine phosphatases (PTPs), the enzymes that catalyze the dephosphorylation of phosphotyrosine residues, are important regulators of mammalian cell signaling, whose activity is misregulated in numerous human diseases. PTPs are also notoriously difficult to selectively modulate with small molecules, and relatively few small-molecule tools for controlling their activities in the context of complex signaling pathways have been developed. Here, we show that a chemical inducer of dimerization (CID) can be used to selectively and potently inhibit constructs of Src-homology-2-containing PTP 2 (SHP2) that have been engineered to contain dimerization domains. Our strategy was inspired by the naturally occurring mechanism of SHP2 regulation, in which the PTP activity of SHP2's catalytic domain is autoinhibited through an intramolecular interaction with the protein's N-terminal SH2 (N-SH2) domain. We have re-engineered this inhibitory interaction to function intermolecularly by independently fusing the SHP2 catalytic and N-SH2 domains to protein domains that heterodimerize upon the introduction of the CID rapamycin. We show that rapamycin-induced protein dimerization leads to potent inhibition of SHP2's catalytic activity, which is driven by increased proximity of the SHP2 catalytic and N-SH2 domains. We also demonstrate that CID-based inhibition of PTP activity can be applied to an oncogenic gain-of-function SHP2 mutant (E76K SHP2) and to the catalytic domain of the SHP2's closest homologue, SHP1. In sum, CID-driven inhibition of PTP activity provides a broadly applicable tool for inhibiting dimerizable forms of the SHP PTPs and represents a novel paradigm for selective PTP inhibition through inducible protein-protein interactions.
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12
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Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways. Toxicol Appl Pharmacol 2022; 441:115988. [DOI: 10.1016/j.taap.2022.115988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/04/2022] [Accepted: 03/14/2022] [Indexed: 12/25/2022]
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Uprety B, Abrahamse H. Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights. Cells 2022; 11:576. [PMID: 35159385 PMCID: PMC8834477 DOI: 10.3390/cells11030576] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells-cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5' adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.
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Affiliation(s)
- Bhawna Uprety
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa;
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14
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Recent Updates on Development of Protein-Tyrosine Phosphatase 1B Inhibitors for Treatment of Diabetes, Obesity and Related Disorders. Bioorg Chem 2022; 121:105626. [DOI: 10.1016/j.bioorg.2022.105626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/19/2021] [Accepted: 01/13/2022] [Indexed: 01/30/2023]
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Liu M, Gao S, Elhassan RM, Hou X, Fang H. Strategies to overcome drug resistance using SHP2 inhibitors. Acta Pharm Sin B 2021; 11:3908-3924. [PMID: 35024315 PMCID: PMC8727779 DOI: 10.1016/j.apsb.2021.03.037] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Encoded by PTPN11, the SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is widely recognized as a carcinogenic phosphatase. As a promising anti-cancer drug target, SHP2 regulates many signaling pathways such as RAS-RAF-ERK, PI3K-AKT and JAK-STAT. Meanwhile, SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment. Heretofore, five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer. Most recently, studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1 (PD-1) blockade. Herein, we review the structure, function and small molecular inhibitors of SHP2, and highlight recent progress in overcoming drug resistance using SHP2 inhibitor. We hope this review would facilitate the future clinical development of SHP2 inhibitors.
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Affiliation(s)
| | | | | | - Xuben Hou
- Corresponding author. Tel./fax: +86 531 88381168.
| | - Hao Fang
- Corresponding author. Tel./fax: +86 531 88381168.
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16
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Sargazi S, Mukhtar M, Rahdar A, Barani M, Pandey S, Díez-Pascual AM. Active Targeted Nanoparticles for Delivery of Poly(ADP-ribose) Polymerase (PARP) Inhibitors: A Preliminary Review. Int J Mol Sci 2021; 22:10319. [PMID: 34638660 PMCID: PMC8508934 DOI: 10.3390/ijms221910319] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Nanotechnology has revolutionized novel drug delivery strategies through establishing nanoscale drug carriers, such as niosomes, liposomes, nanomicelles, dendrimers, polymeric micelles, and nanoparticles (NPs). Owing to their desirable cancer-targeting efficacy and controlled release, these nanotherapeutic modalities are broadly used in clinics to improve the efficacy of small-molecule inhibitors. Poly(ADP-ribose) polymerase (PARP) family members engage in various intracellular processes, including DNA repair, gene transcription, signal transduction, cell cycle regulation, cell division, and antioxidant response. PARP inhibitors are synthetic small-molecules that have emerged as one of the most successful innovative strategies for targeted therapy in cancer cells harboring mutations in DNA repair genes. Despite these advances, drug resistance and unwanted side effects are two significant drawbacks to using PARP inhibitors in the clinic. Recently, the development of practical nanotechnology-based drug delivery systems has tremendously improved the efficacy of PARP inhibitors. NPs can specifically accumulate in the leaky vasculature of the tumor and cancer cells and release the chemotherapeutic moiety in the tumor microenvironment. On the contrary, NPs are usually unable to permeate across the body's normal organs and tissues; hence the toxicity is zero to none. NPs can modify the release of encapsulated drugs based on the composition of the coating substance. Delivering PARP inhibitors without modulation often leads to the toxic effect; therefore, a delivery vehicle is essential to encapsulate them. Various nanocarriers have been exploited to deliver PARP inhibitors in different cancers. Through this review, we hope to cast light on the most innovative advances in applying PARP inhibitors for therapeutic purposes.
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Affiliation(s)
- Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan 9816743463, Iran;
| | - Mahwash Mukhtar
- Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary;
| | - Abbas Rahdar
- Department of Physics, Faculty of Science, University of Zabol, Zabol 538-98615, Iran;
| | - Mahmood Barani
- Medical Mycology and Bacteriology Research Center, Kerman University of Medical Sciences, Kerman 7616913555, Iran;
| | - Sadanad Pandey
- Department of Chemistry, College of Natural Science, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Korea; or
| | - Ana M. Díez-Pascual
- Universidad de Alcalá, Facultad de Ciencias, Departamento de Química Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona, Km. 33.6, 28805 Alcalá de Henares, Madrid, Spain
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17
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Wang D, Tang F, Liu X, Fan Y, Zheng Y, Zhuang H, Chen B, Zhuo J, Wang B. Expression and Tumor-Promoting Effect of Tyrosine Phosphatase Receptor Type N (PTPRN) in Human Glioma. Front Oncol 2021; 11:676287. [PMID: 34557405 PMCID: PMC8453168 DOI: 10.3389/fonc.2021.676287] [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: 03/05/2021] [Accepted: 07/09/2021] [Indexed: 01/26/2023] Open
Abstract
Tyrosine phosphatase receptor type N (PTPRN) plays an important role in the regulation of the secretion pathways of various neuroendocrine cells. Moreover, PTPRN was demonstrated to play a crucial role in the initiation and progression of the signalling cascade regulating cell function. In this study, fifty-seven glioma patients were enrolled for clinical and prognostic analyses. The cell phenotype was determined by cell proliferation and migration assays. RNA-seq, co-IP and mass spectrometry were used to study the molecular mechanism of the effects of PTPRN on cell proliferation and metastasis. The result showed that High expression of PTPRN indicated a poor prognosis of high-grade glioma. PTPRN downregulation reduced the proliferation and migration of glioma cells, and PTPRN overexpression induced the proliferation and migration of glioma cells. PTPRN knockdown decreased tumor growth in a mouse xenograft model. Effect of PTPRN knockdown on the transcriptome was studied in U87 glioma cells. PTPRN activated the PI3K/AKT pathway by interacting with HSP90AA1. In conclusion, PTPRN is an important proliferation- and metastasis-promoting factor. Reducing the expression of PTPRN in glioma cells can be used as a potential therapeutic strategy.
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Affiliation(s)
- Dong Wang
- Department of Neurosurgery, Tianjin Medical University, General Hospital, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China
| | - Fan Tang
- Department of Pathology, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Yueshan Fan
- Department of Neurosurgery, Tianjin Medical University, General Hospital, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China
| | - Yu Zheng
- GCP Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Hao Zhuang
- Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Budong Chen
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China.,Department of Neurosurgery, Tianjin University Huanhu Hospital, Tianjin, China.,Department of Neurosurgery, Huanhu Hospital Affiliated to Nankai University, Tianjin, China
| | - Jie Zhuo
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China.,Department of Neurosurgery, Tianjin University Huanhu Hospital, Tianjin, China.,Department of Neurosurgery, Huanhu Hospital Affiliated to Nankai University, Tianjin, China
| | - Bo Wang
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China.,Department of Neurosurgery, Tianjin University Huanhu Hospital, Tianjin, China.,Department of Neurosurgery, Huanhu Hospital Affiliated to Nankai University, Tianjin, China
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18
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The dual inhibition against the activity and expression of tyrosine phosphatase PRL-3 from a rhodanine derivative. Bioorg Med Chem Lett 2021; 41:127981. [PMID: 33766767 DOI: 10.1016/j.bmcl.2021.127981] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/12/2021] [Accepted: 03/14/2021] [Indexed: 11/22/2022]
Abstract
Increasing evidences demonstrated that PRL-3 was associated with metastatic potential in a variety of cancers including CRC, gastric cancer, ovarian cancer and so on. PRL-3 knock down inhibited the development of metastasis by reducing the size of primary tumors and inhibiting the invasion and growth of cancer cells. Therefore, PRL-3 is a promising diagnostic marker and therapeutic target in tumors. So far, only several PRL-3 inhibitors have been reported. In this study, six rhodanine derivatives were synthesized and characterized. The compounds were evaluated against tyrosine phosphatase PRL-3. Among these compounds, 5-(5-chloro-2-(trifluoromethyl)benzylidene)-2-thioxothiazolidin-4-one (4) could effectively inhibit PRL-3 with IC50 value of 15.22 μM. Fluorescent assays suggested compound 4 tightly bound to tyrosine phosphatase PRL-3 with the molar ratio of 1:1, and the binding constant of 1.74 × 106 M-1. Compound 4 entered into SW-480 cells, selectively inhibited the expression of PRL-3 and increased the phosphorylation of PRL-3 substrates, and decreased the survival rate of SW-480 cells with IC50 of 6.64 μM and induced apoptosis. The results revealed that compound 4 is a dual functional inhibitor against the activity and expression of PRL-3 and a promising anti-cancer candidate targeting PRL-3.
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19
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Lambert LJ, Grotegut S, Celeridad M, Gosalia P, Backer LJSD, Bobkov AA, Salaniwal S, Chung TDY, Zeng FY, Pass I, Lombroso PJ, Cosford NDP, Tautz L. Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP). Int J Mol Sci 2021; 22:ijms22094417. [PMID: 33922601 PMCID: PMC8122956 DOI: 10.3390/ijms22094417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/14/2021] [Accepted: 04/20/2021] [Indexed: 12/16/2022] Open
Abstract
Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.
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Affiliation(s)
- Lester J Lambert
- Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (L.J.L.); (M.C.); (L.J.D.B.); (N.D.C.)
| | - Stefan Grotegut
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Maria Celeridad
- Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (L.J.L.); (M.C.); (L.J.D.B.); (N.D.C.)
| | - Palak Gosalia
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Laurent JS De Backer
- Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (L.J.L.); (M.C.); (L.J.D.B.); (N.D.C.)
| | - Andrey A Bobkov
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Sumeet Salaniwal
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Thomas DY Chung
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Fu-Yue Zeng
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Ian Pass
- Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (S.G.); (P.G.); (A.A.B.); (S.S.); (T.D.C.); (F.-Y.Z.); (I.P.)
| | - Paul J Lombroso
- Child Study Center, Departments of Psychiatry and Departments of Neurobiology, Yale University, 230 South Frontage Rd, New Haven, CT 06520, USA;
| | - Nicholas DP Cosford
- Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (L.J.L.); (M.C.); (L.J.D.B.); (N.D.C.)
| | - Lutz Tautz
- Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA; (L.J.L.); (M.C.); (L.J.D.B.); (N.D.C.)
- Correspondence:
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A Crosstalk Between Dual-Specific Phosphatases and Dual-Specific Protein Kinases Can Be A Potential Therapeutic Target for Anti-cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:357-382. [PMID: 33539023 DOI: 10.1007/978-3-030-49844-3_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
While protein tyrosine kinases (PTKs) play an initiative role in growth factor-mediated cellular processes, protein tyrosine phosphatases (PTPs) negatively regulates these processes, acting as tumor suppressors. Besides selective tyrosine dephosphorylation of PTKs via PTPs may affect oncogenic pathways during carcinogenesis. The PTP family contains a group of dual-specificity phosphatases (DUSPs) that regulate the activity of Mitogen-activated protein kinases (MAPKs), which are key effectors in the control of cell growth, proliferation and survival. Abnormal MAPK signaling is critical for initiation and progression stages of carcinogenesis. Since depletion of DUSP-MAPK phosphatases (MKPs) can reduce tumorigenicity, altering MAPK signaling by DUSP-MKP inhibitors could be a novel strategy in anti-cancer therapy. Moreover, Cdc25A is, a DUSP and a key regulator of the cell cycle, promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases (CDK). Cdc25A-CDK pathway is a novel mechanism in carcinogenesis. Besides the mammalian target of rapamycin (mTOR) kinase inhibitors or mammalian target of rapamycin complex 1 (mTORC1) inhibition in combination with the dual phosphatidylinositol 3 kinase (PI3K)/mTOR or AKT kinase inhibitors are more effective in inhibiting the phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and cap-dependent translation. Dual targeting of the Akt and mTOR signaling pathways regulates cellular growth, proliferation and survival. Like the Cdc2-like kinases (CLK), dual-specific tyrosine phosphorylation-regulated kinases (DYRKs) are essential for the regulation of cell fate. The crosstalk between dual-specific phosphatases and dual- specific protein kinases is a novel drug target for anti-cancer therapy. Therefore, the focus of this chapter involves protein kinase modules, critical biochemical checkpoints of cancer therapy and the synergistic effects of protein kinases and anti-cancer molecules.
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Mitra R, Ayyannan SR. Small-Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview. ChemMedChem 2020; 16:777-787. [PMID: 33210828 DOI: 10.1002/cmdc.202000706] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/13/2020] [Indexed: 12/13/2022]
Abstract
Glioblastoma multiforme (GBM) is a dreadful cancer characterised by poor prognosis, low survival rate and difficult clinical correlations. Several signalling pathways and molecular mediators are known to precipitate GBM, and small-molecular targets of these mediators have become a favoured thrust area for researchers to develop potent anti-GBM drugs. Shp2, an important phosphatase of the nonreceptor type protein tyrosine phosphatase (PTPN) subfamily is responsible for master regulation of several such signalling pathways in normal and glioma cells. Thus, inhibition of Shp2 is a logical strategy for the design and development of anti-neoplastic drugs against GBM. Though tapping the full potential of Shp2 binding sites has been challenging, nevertheless, many synthetic and natural scaffolds have been documented as possessing potent and selective anti-Shp2 activities in biochemical and cellular assays, through either active-site or allosteric binding. Most of these scaffolds share a few common pharmacophoric features, a thorough study of which is useful in paving the way for the design and development of improved Shp2 inhibitors. This minireview summarizes the current scenario of potent small-molecule Shp2 inhibitors and emphasizes the anti-GBM potential of some important scaffolds that have shown promising GBM-specific activity in in vitro and in vivo models, thus proving their efficacy in GBM therapy. This review could guide researchers to design new and improved anti-Shp2 pharmacophores and develop them as anti-GBM agents by employing GBM-centric drug-discovery protocols.
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Affiliation(s)
- Rangan Mitra
- Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, Uttar Pradesh, India
| | - Senthil R Ayyannan
- Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, Uttar Pradesh, India
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Pardella E, Pranzini E, Leo A, Taddei ML, Paoli P, Raugei G. Oncogenic Tyrosine Phosphatases: Novel Therapeutic Targets for Melanoma Treatment. Cancers (Basel) 2020; 12:E2799. [PMID: 33003469 PMCID: PMC7599540 DOI: 10.3390/cancers12102799] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/12/2022] Open
Abstract
Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches. Collectively, this information highlights the value of going further in the development of new strategies targeting oncogenic PTPs to improve the efficacy of melanoma treatment.
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Affiliation(s)
- Elisa Pardella
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio” University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (E.P.); (E.P.); (A.L.); (G.R.)
| | - Erica Pranzini
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio” University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (E.P.); (E.P.); (A.L.); (G.R.)
| | - Angela Leo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio” University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (E.P.); (E.P.); (A.L.); (G.R.)
| | - Maria Letizia Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134 Florence, Italy;
| | - Paolo Paoli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio” University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (E.P.); (E.P.); (A.L.); (G.R.)
| | - Giovanni Raugei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio” University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (E.P.); (E.P.); (A.L.); (G.R.)
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Kumar A, Rana D, Rana R, Bhatia R. Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments. Curr Mol Pharmacol 2020; 13:17-30. [DOI: 10.2174/1874467212666190724150723] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/26/2019] [Accepted: 07/11/2019] [Indexed: 12/14/2022]
Abstract
Background:Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors.Objective:In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus.Conclusion:There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.
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Affiliation(s)
- Ajay Kumar
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Divya Rana
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Rajat Rana
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Rohit Bhatia
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
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24
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Plaman BA, Chan WC, Bishop AC. Chemical activation of divergent protein tyrosine phosphatase domains with cyanine-based biarsenicals. Sci Rep 2019; 9:16148. [PMID: 31695052 PMCID: PMC6834593 DOI: 10.1038/s41598-019-52002-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 10/11/2019] [Indexed: 12/28/2022] Open
Abstract
Strategies for the direct chemical activation of specific signaling proteins could provide powerful tools for interrogating cellular signal transduction. However, targeted protein activation is chemically challenging, and few broadly applicable activation strategies for signaling enzymes have been developed. Here we report that classical protein tyrosine phosphatase (PTP) domains from multiple subfamilies can be systematically sensitized to target-specific activation by the cyanine-based biarsenical compounds AsCy3 and AsCy5. Engineering of the activatable PTPs (actPTPs) is achieved by the introduction of three cysteine residues within a conserved loop of the PTP domain, and the positions of the sensitizing mutations are readily identifiable from primary sequence alignments. In the current study we have generated and characterized actPTP domains from three different subfamilies of both receptor and non-receptor PTPs. Biarsenical-induced stimulation of the actPTPs is rapid and dose-dependent, and is operative with both purified enzymes and complex proteomic mixtures. Our results suggest that a substantial fraction of the classical PTP family will be compatible with the act-engineering approach, which provides a novel chemical-biological tool for the control of PTP activity and the study of PTP function.
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Affiliation(s)
- Bailey A Plaman
- Amherst College, Department of Chemistry, Amherst, Massachusetts, 01002, USA
| | - Wai Cheung Chan
- Amherst College, Department of Chemistry, Amherst, Massachusetts, 01002, USA.,Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, MA, 02215, USA
| | - Anthony C Bishop
- Amherst College, Department of Chemistry, Amherst, Massachusetts, 01002, USA.
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25
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Modaresi S, Pacelli S, Subham S, Dathathreya K, Paul A. Intracellular Delivery of Exogenous Macromolecules into Human Mesenchymal Stem Cells by Double Deformation of the Plasma Membrane. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900130] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Saman Modaresi
- Department of Chemical and Petroleum EngineeringBioIntel Research LaboratoryUniversity of Kansas Lawrence KS 66045 USA
| | - Settimio Pacelli
- Department of Chemical and Petroleum EngineeringBioIntel Research LaboratoryUniversity of Kansas Lawrence KS 66045 USA
| | - Siddharth Subham
- Department of Chemical and Petroleum EngineeringBioIntel Research LaboratoryUniversity of Kansas Lawrence KS 66045 USA
| | - Kavya Dathathreya
- Department of Chemical and Petroleum EngineeringBioIntel Research LaboratoryUniversity of Kansas Lawrence KS 66045 USA
| | - Arghya Paul
- Department of Chemical and Petroleum EngineeringBioIntel Research LaboratoryUniversity of Kansas Lawrence KS 66045 USA
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26
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Ruckert MT, de Andrade PV, Santos VS, Silveira VS. Protein tyrosine phosphatases: promising targets in pancreatic ductal adenocarcinoma. Cell Mol Life Sci 2019; 76:2571-2592. [PMID: 30982078 PMCID: PMC11105579 DOI: 10.1007/s00018-019-03095-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 03/25/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is the fourth leading cause of cancer-related death and is associated with a very poor prognosis. KRAS driver mutations occur in approximately 95% of PDAC cases and cause the activation of several signaling pathways such as mitogen-activated protein kinase (MAPK) pathways. Regulation of these signaling pathways is orchestrated by feedback loops mediated by the balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), leading to activation or inhibition of its downstream targets. The human PTPome comprises 125 members, and these proteins are classified into three distinct families according to their structure. Since PTP activity description, it has become clear that they have both inhibitory and stimulatory effects on cancer-associated signaling processes and that deregulation of PTP function is closely associated with tumorigenesis. Several PTPs have displayed either tumor suppressor or oncogenic characteristics during the development and progression of PDAC. In this sense, PTPs have been presented as promising candidates for the treatment of human pancreatic cancer, and many PTP inhibitors have been developed since these proteins were first associated with cancer. Nevertheless, some challenges persist regarding the development of effective and safe methods to target these molecules and deliver these drugs. In this review, we discuss the role of PTPs in tumorigenesis as tumor suppressor and oncogenic proteins. We have focused on the differential expression of these proteins in PDAC, as well as their clinical implications and possible targeting for pharmacological inhibition in cancer therapy.
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Affiliation(s)
- Mariana Tannús Ruckert
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil
| | - Pamela Viani de Andrade
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil
| | - Verena Silva Santos
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil
| | - Vanessa Silva Silveira
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil.
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27
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Marsh-Armstrong B, Fajnzylber JM, Korntner S, Plaman BA, Bishop AC. The Allosteric Site on SHP2's Protein Tyrosine Phosphatase Domain is Targetable with Druglike Small Molecules. ACS OMEGA 2018; 3:15763-15770. [PMID: 30533581 PMCID: PMC6275946 DOI: 10.1021/acsomega.8b02200] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/23/2018] [Indexed: 06/09/2023]
Abstract
Difficulties in developing active-site-directed protein tyrosine phosphatase (PTP) inhibitors have led to the perception that PTPs are "undruggable", highlighting the need for new means to target pharmaceutically important PTPs allosterically. Recently, we characterized an allosteric-inhibition site on the PTP domain of Src-homology-2-domain-containing PTP 2 (SHP2), a key anticancer drug target. The central feature of SHP2's allosteric site is a nonconserved cysteine residue (C333) that can potentially be labeled with electrophilic compounds for selective SHP2 inhibition. Here, we describe the first directed discovery effort for C333-targeted allosteric SHP2 inhibitors. By screening a previously reported library of reversible, covalent inhibitors, we identified a lead compound, which was modified to yield an irreversible inhibitor (12), that inhibits SHP2 allosterically and selectively through interaction with C333. These findings provide a novel paradigm for allosteric-inhibitor discovery on SHP2, one that may help to circumvent the challenges inherent in targeting SHP2's active site.
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28
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Ha MT, Park DH, Shrestha S, Kim M, Kim JA, Woo MH, Choi JS, Min BS. PTP1B inhibitory activity and molecular docking analysis of stilbene derivatives from the rhizomes of Rheum undulatum L. Fitoterapia 2018; 131:119-126. [PMID: 30352293 DOI: 10.1016/j.fitote.2018.10.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022]
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29
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Abbasi M, Gupta V, Chitranshi N, You Y, Dheer Y, Mirzaei M, Graham SL. Regulation of Brain-Derived Neurotrophic Factor and Growth Factor Signaling Pathways by Tyrosine Phosphatase Shp2 in the Retina: A Brief Review. Front Cell Neurosci 2018; 12:85. [PMID: 29636665 PMCID: PMC5880906 DOI: 10.3389/fncel.2018.00085] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/09/2018] [Indexed: 01/31/2023] Open
Abstract
SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2) is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF) signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK) pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF) neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina.
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Affiliation(s)
- Mojdeh Abbasi
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Vivek Gupta
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nitin Chitranshi
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Yuyi You
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Yogita Dheer
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mehdi Mirzaei
- Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia.,Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia
| | - Stuart L Graham
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
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30
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PTP1B inhibitory and cytotoxic activities of triterpenoids from the aerial parts of Agrimonia pilosa. Med Chem Res 2017. [DOI: 10.1007/s00044-017-1986-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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31
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Meng G, Zheng M, Wang M, Tong J, Ge W, Zhang J, Zheng A, Li J, Gao L, Li J. Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I. Eur J Med Chem 2016; 122:756-769. [PMID: 27526040 DOI: 10.1016/j.ejmech.2016.05.060] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/26/2016] [Accepted: 05/26/2016] [Indexed: 11/19/2022]
Abstract
A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group. Compound 14b, 14h and 14i showed IC50 values of 8.66 μM, 6.83 μM and 6.09 μM against PTP1B, respectively. Docking analysis of these active compounds with PTP1B showed the possible interaction modes of these biheterocyclic compounds with the active sites of PTP1B. The inhibition tests against oncogenetic CDC25B were also conducted on this set of compounds to evaluate the selectivity and possible anti-neoplastic activity. Compound 14b also showed the lowest IC50 of 1.66 μM against CDC25B among all the possible inhibitors, including 14g, 14h, 14i and 15c. Some pharmacological parameters including VolSurf, steric and electric descriptors of all the compounds were calculated to give some hints about the relative relationship with the biological activity. The result of this study might give some light on designing the possible anti-cancer drugs targeting at phosphatases. The most active compound 14i might be used as the lead compound for further structure modification of the new low molecular weight PTP1B inhibitors with the N-containing heterocyclic skeleton.
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Affiliation(s)
- Ge Meng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China.
| | - Meilin Zheng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China
| | - Mei Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China
| | - Jing Tong
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China
| | - Weijuan Ge
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China
| | - Jiehe Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi, 710061, PR China
| | - Aqun Zheng
- School of Science, Xi'an Jiaotong University, No. 28, Xianning West Road, Xi'an, Shaanxi, 710049, PR China
| | - Jingya Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
| | - Lixin Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
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32
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Li Y, Xia G, Guo Q, Wu L, Chen S, Yang Z, Wang W, Zhang ZY, Zhou X, Jiang ZX. Design, synthesis and evaluation of novel 19F magnetic resonance sensitive protein tyrosine phosphatase inhibitors. MEDCHEMCOMM 2016; 7:1672-1680. [PMID: 27529021 DOI: 10.1039/c6md00277c] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Fluorine is a highly attractive element for both medicinal chemistry and imaging technologies. To facilitate protein tyrosine phosphatases (PTPs)-targeted drug discovery and imaging-guided PTP research with fluorine, several highly potent and 19F MR sensitive PTP inhibitors were discovered through a structure-based focused library strategy.
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Affiliation(s)
- Yu Li
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Guiquan Xia
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Qi Guo
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Li Wu
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA
| | - Shizhen Chen
- State Key Laboratory for Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China
| | - Zhigang Yang
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Wei Wang
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA
| | - Xin Zhou
- State Key Laboratory for Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China
| | - Zhong-Xing Jiang
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; State Key Laboratory for Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai 201620, China
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33
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Selective Sensing of Tyrosine Phosphorylation in Peptides Using Terbium(III) Complexes. Int J Anal Chem 2016; 2016:3216523. [PMID: 27375742 PMCID: PMC4916314 DOI: 10.1155/2016/3216523] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/28/2016] [Indexed: 11/18/2022] Open
Abstract
Phosphorylation of tyrosine residues in proteins, as well as their dephosphorylation, is closely related to various diseases. However, this phosphorylation is usually accompanied by more abundant phosphorylation of serine and threonine residues in the proteins and covers only 0.05% of the total phosphorylation. Accordingly, highly selective detection of phosphorylated tyrosine in proteins is an urgent subject. In this review, recent developments in this field are described. Monomeric and binuclear Tb(III) complexes, which emit notable luminescence only in the presence of phosphotyrosine (pTyr), have been developed. There, the benzene ring of pTyr functions as an antenna and transfers its photoexcitation energy to the Tb(III) ion as the emission center. Even in the coexistence of phosphoserine (pSer) and phosphothreonine (pThr), pTyr can be efficintly detected with high selectivity. Simply by adding these Tb(III) complexes to the solutions, phosphorylation of tyrosine in peptides by protein tyrosine kinases and dephosphorylation by protein tyrosine phosphatases can be successfully visualized in a real-time fashion. Furthermore, the activities of various inhibitors on these enzymes are quantitatively evaluated, indicating a strong potential of the method for efficient screening of eminent inhibitors from a number of candidates.
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Maeshima K, Stanford SM, Hammaker D, Sacchetti C, Zeng LF, Ai R, Zhang V, Boyle DL, Aleman Muench GR, Feng GS, Whitaker JW, Zhang ZY, Wang W, Bottini N, Firestein GS. Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 2016; 1. [PMID: 27275015 DOI: 10.1172/jci.insight.86580] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer and PTPN11 expression. Glucocorticoid responsiveness of PTPN11 was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygous Ptpn11 deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA.
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Affiliation(s)
- Keisuke Maeshima
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA
| | - Stephanie M Stanford
- Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Deepa Hammaker
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA
| | - Cristiano Sacchetti
- Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Li-Fan Zeng
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Rizi Ai
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA
| | - Vida Zhang
- Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - David L Boyle
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA
| | - German R Aleman Muench
- Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Gen-Sheng Feng
- Department of Pathology and Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA
| | - John W Whitaker
- Janssen Pharmaceuticals Companies of Johnson and Johnson, La Jolla, California, USA
| | - Zhong-Yin Zhang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Wei Wang
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA
| | - Nunzio Bottini
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.; Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Gary S Firestein
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA
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35
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Song GJ, Jung M, Kim JH, Park H, Rahman MH, Zhang S, Zhang ZY, Park DH, Kook H, Lee IK, Suk K. A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. J Neuroinflammation 2016; 13:86. [PMID: 27095436 PMCID: PMC4837589 DOI: 10.1186/s12974-016-0545-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 04/11/2016] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Protein tyrosine phosphatase 1B (PTP1B) is a member of the non-transmembrane phosphotyrosine phosphatase family. Recently, PTP1B has been proposed to be a novel target of anti-cancer and anti-diabetic drugs. However, the role of PTP1B in the central nervous system is not clearly understood. Therefore, in this study, we sought to define PTP1B's role in brain inflammation. METHODS PTP1B messenger RNA (mRNA) and protein expression levels were examined in mouse brain and microglial cells after LPS treatment using RT-PCR and western blotting. Pharmacological inhibitors of PTP1B, NF-κB, and Src kinase were used to analyze these signal transduction pathways in microglia. A Griess reaction protocol was used to determine nitric oxide (NO) concentrations in primary microglia cultures and microglial cell lines. Proinflammatory cytokine production was measured by RT-PCR. Western blotting was used to assess Src phosphorylation levels. Immunostaining for Iba-1 was used to determine microglial activation in the mouse brain. RESULTS PTP1B expression levels were significantly increased in the brain 24 h after LPS injection, suggesting a functional role for PTP1B in brain inflammation. Microglial cells overexpressing PTP1B exhibited an enhanced production of NO and gene expression levels of TNF-α, iNOS, and IL-6 following LPS exposure, suggesting that PTP1B potentiates the microglial proinflammatory response. To confirm the role of PTP1B in neuroinflammation, we employed a highly potent and selective inhibitor of PTP1B (PTP1Bi). In LPS- or TNF-α-stimulated microglial cells, in vitro blockade of PTP1B activity using PTP1Bi markedly attenuated NO production. PTP1Bi also suppressed the expression levels of iNOS, COX-2, TNF-α, and IL-1β. PTP1B activated Src by dephosphorylating the Src protein at a negative regulatory site. PTP1B-mediated Src activation led to an enhanced proinflammatory response in the microglial cells. An intracerebroventricular injection of PTP1Bi significantly attenuated microglial activation in the hippocampus and cortex of LPS-injected mice compared to vehicle-injected mice. The gene expression levels of proinflammatory cytokines were also significantly suppressed in the brain by a PTP1Bi injection. Together, these data suggest that PTP1Bi has an anti-inflammatory effect in a mouse model of neuroinflammation. CONCLUSIONS This study demonstrates that PTP1B is an important positive regulator of neuroinflammation and is a promising therapeutic target for neuroinflammatory and neurodegenerative diseases.
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Affiliation(s)
- Gyun Jee Song
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Myungsu Jung
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Jong-Heon Kim
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Hana Park
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Md Habibur Rahman
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Sheng Zhang
- />Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907 USA
| | - Zhong-Yin Zhang
- />Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907 USA
| | - Dong Ho Park
- />Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Hyun Kook
- />Department of Pharmacology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - In-Kyu Lee
- />Department of Internal Medicine, Division of Endocrinology and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Kyoungho Suk
- />Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
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Fontanillo M, Köhn M. Phosphatases: Their Roles in Cancer and Their Chemical Modulators. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 917:209-40. [PMID: 27236558 DOI: 10.1007/978-3-319-32805-8_10] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Phosphatases are involved in basically all cellular processes by dephosphorylating cellular components such as proteins, phospholipids and second messengers. They counteract kinases of which many are established oncogenes, and therefore kinases are one of the most important drug targets for targeted cancer therapy. Due to this relationship between kinases and phosphatases, phosphatases are traditionally assumed to be tumour suppressors. However, research findings over the last years prove that this simplification is incorrect, as bona-fide and putative phosphatase oncogenes have been identified. We describe here the role of phosphatases in cancer, tumour suppressors and oncogenes, and their chemical modulators, and discuss new approaches and opportunities for phosphatases as drug targets.
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Affiliation(s)
- Miriam Fontanillo
- Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany
| | - Maja Köhn
- Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
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37
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Baburajeev CP, Dhananjaya Mohan C, Ananda H, Rangappa S, Fuchs JE, Jagadish S, Sivaraman Siveen K, Chinnathambi A, Ali Alharbi S, Zayed ME, Zhang J, Li F, Sethi G, Girish KS, Bender A, Basappa, Rangappa KS. Development of Novel Triazolo-Thiadiazoles from Heterogeneous "Green" Catalysis as Protein Tyrosine Phosphatase 1B Inhibitors. Sci Rep 2015; 5:14195. [PMID: 26388336 PMCID: PMC4585680 DOI: 10.1038/srep14195] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 08/18/2015] [Indexed: 02/06/2023] Open
Abstract
Condensed-bicyclic triazolo-thiadiazoles were synthesized via an efficient "green" catalyst strategy and identified as effective inhibitors of PTP1B in vitro. The lead compound, 6-(2-benzylphenyl)-3-phenyl-[1,2,4]triazolo[3][1,3,4]thiadiazole (BPTT) was most effective against human hepatoma cells, inhibits cell invasion, and decreases neovasculature in HUVEC and also tumor volume in EAT mouse models. This report describes an experimentally unidentified class of condensed-bicyclic triazolo-thiadiazoles targeting PTP1B and its analogs could be the therapeutic drug-seeds.
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Affiliation(s)
- C P Baburajeev
- Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India
| | | | - Hanumappa Ananda
- Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, India
| | - Shobith Rangappa
- Frontier Research Center for Post-genome Science and Technology, Hokkaido University, Sapporo 0600808, Japan
| | - Julian E Fuchs
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom
| | - Swamy Jagadish
- Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, India
| | - Kodappully Sivaraman Siveen
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore-117597, Singapore
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saudi University, Riyadh -11451, Kingdom of Saudi Arabia
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saudi University, Riyadh -11451, Kingdom of Saudi Arabia
| | - M E Zayed
- Department of Botany and Microbiology, College of Science, King Saudi University, Riyadh -11451, Kingdom of Saudi Arabia
| | - Jingwen Zhang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore-117597, Singapore
| | - Feng Li
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore-117597, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore-117597, Singapore
| | - Kesturu S Girish
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-570006, India
| | - Andreas Bender
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom
| | - Basappa
- Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India
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38
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Kobayashi M, Chen S, Gao R, Bai Y, Zhang ZY, Liu Y. Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies. Cell Cycle 2015; 13:2827-35. [PMID: 25486470 DOI: 10.4161/15384101.2014.954448] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The phosphatases of regenerating liver (PRLs), consisting PRL1, PRL2 and PRL3, are dual-specificity protein phosphatases that have been implicated as biomarkers and therapeutic targets in several solid tumors. However, their roles in hematological malignancies are largely unknown. Recent findings demonstrate that PRL2 is important for hematopoietic stem cell self-renewal and proliferation. In addition, both PRL2 and PRL3 are highly expressed in some hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Moreover, PRL deficiency impairs the proliferation and survival of leukemia cells through regulating oncogenic signaling pathways. While PRLs are potential novel therapeutic targets in hematological malignancies, their exact biological function and cellular substrates remain unclear. This review will discuss how PRLs regulate hematopoietic stem cell behavior, what signaling pathways are regulated by PRLs, and how to target PRLs in hematological malignancies. An improved understanding of how PRLs function and how they are regulated may facilitate the development of PRL inhibitors that are effective in cancer treatment.
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Affiliation(s)
- Michihiro Kobayashi
- a Department of Pediatrics, Herman B Wells Center for Pediatric Research; Department of Biochemistry and Molecular Biology , Indiana University School of Medicine ; Indianapolis , IN USA
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39
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Liu L, Zhang J, Chen C, Teng J, Wang C, Luo D. Structure and biosynthesis of fumosorinone, a new protein tyrosine phosphatase 1B inhibitor firstly isolated from the entomogenous fungus Isaria fumosorosea. Fungal Genet Biol 2015; 81:191-200. [DOI: 10.1016/j.fgb.2015.03.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 03/26/2015] [Accepted: 03/30/2015] [Indexed: 11/24/2022]
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40
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Fonseca EMB, Trivella DBB, Scorsato V, Dias MP, Bazzo NL, Mandapati KR, de Oliveira FL, Ferreira-Halder CV, Pilli RA, Miranda PCML, Aparicio R. Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates. Bioorg Med Chem 2015; 23:4462-4471. [PMID: 26117648 DOI: 10.1016/j.bmc.2015.06.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 05/29/2015] [Accepted: 06/05/2015] [Indexed: 12/22/2022]
Abstract
Low molecular weight protein tyrosine phosphatases (LMW-PTP, EC 3.1.3.48) are a family of single-domain enzymes with molecular weight up to 18 kDa, expressed in different tissues and considered attractive pharmacological targets for cancer chemotherapy. Despite this, few LMW-PTP inhibitors have been described to date, and the structural information on LMW-PTP druggable binding sites is scarce. In this study, a small series of phosphonic acids were designed based on a new crystallographic structure of LMW-PTP complexed with benzylsulfonic acid, determined at 2.1Å. In silico docking was used as a tool to interpret the structural and enzyme kinetics data, as well as to design new analogs. From the synthesized series, two compounds were found to act as competitive inhibitors, with inhibition constants of 0.124 and 0.047 mM. We also report the 2.4Å structure of another complex in which LMW-PTP is bound to benzylphosphonic acid, and a structure of apo LMW-PTP determined at 2.3Å resolution. Although no appreciable conformation changes were observed, in the latter structures, amino acid residues from an expression tag were found bound to a hydrophobic region at the protein surface. This regions is neighbored by positively charged residues, adjacent to the active site pocket, suggesting that this region might be not a mere artefact of crystal contacts but an indication of a possible anchoring region for the natural substrate-which is a phosphorylated protein.
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Affiliation(s)
- Emanuella M B Fonseca
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil
| | - Daniela B B Trivella
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil; Department of Organic Chemistry, Institute of Chemistry, University of Campinas, CP 6154, CEP 13083-970, Campinas, SP, Brazil
| | - Valéria Scorsato
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil
| | - Mariana P Dias
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil
| | - Natália L Bazzo
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil
| | - Kishore R Mandapati
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil; Department of Organic Chemistry, Institute of Chemistry, University of Campinas, CP 6154, CEP 13083-970, Campinas, SP, Brazil
| | - Fábio L de Oliveira
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil
| | - Carmen V Ferreira-Halder
- Department of Biochemistry, Institute of Biology, University of Campinas, CEP 13083-862, Campinas, SP, Brazil
| | - Ronaldo A Pilli
- Department of Organic Chemistry, Institute of Chemistry, University of Campinas, CP 6154, CEP 13083-970, Campinas, SP, Brazil
| | - Paulo C M L Miranda
- Department of Organic Chemistry, Institute of Chemistry, University of Campinas, CP 6154, CEP 13083-970, Campinas, SP, Brazil
| | - Ricardo Aparicio
- Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil.
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Clark O, Park I, Di Florio A, Cichon AC, Rustin S, Jugov R, Maeshima R, Stoker AW. Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine. Cancer Lett 2014; 357:316-327. [PMID: 25444896 DOI: 10.1016/j.canlet.2014.11.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 11/17/2014] [Accepted: 11/18/2014] [Indexed: 12/30/2022]
Abstract
In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.
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Affiliation(s)
- Owen Clark
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Inhye Park
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Alessia Di Florio
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Ann-Christin Cichon
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Sarah Rustin
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Roman Jugov
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Ruhina Maeshima
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Andrew W Stoker
- Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
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42
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Jung KJ, Lee EK, Kim SJ, Song CW, Maruyama N, Ishigami A, Kim ND, Im DS, Yu BP, Chung HY. Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance. J Mol Med (Berl) 2014; 93:343-56. [PMID: 25394676 DOI: 10.1007/s00109-014-1219-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 09/25/2014] [Accepted: 10/23/2014] [Indexed: 10/24/2022]
Abstract
UNLABELLED Recent studies on senescence marker protein-30 (SMP30) have shown that it has an important functional role in the aging process, but its precise participation in cellular works has not been fully determined. We hypothesize that SMP30 plays crucial roles in signaling processes by modulating the balance of protein tyrosine kinase (PTK)/protein tyrosine phosphatase (PTP) and in activating proinflammatory NF-κB. An experimental paradigm of gain and loss of SMP30 function was established using SMP30-overexpressed YPEN-1 cells (herein referred to as "SMP30(+) cells") and SMP30 (Y/-) knockout mouse kidneys. The resulting data show that SMP30 expression suppressed oxidative stress-induced PTK/PTP dysregulation and PP1/2A inactivation in SMP30(+) cells, leading to the suppression of NF-κB activation. In the kidneys of SMP30 (Y/-) mice, SMP30 deficiency was found to induce NF-κB activation via the upstream signaling of NIK/IKK and MAPKs and to upregulate downstream NF-κB-responsive gene expression. In this study, we also demonstrate for the first time that SMP30 deficiency induced PTK activity in SMP30 (Y/-) kidneys, thereby significantly increasing the tyrosine phosphorylation of a catalytic subunit of PP2A (PP2Ac-Tyr307). Based on these findings, we propose that SMP30 involves NF-κB regulation through the PTK/PTP balance and that the age-related decrease of SMP30 causes NF-κB activation, which contributes to an exacerbation of the inflammatory process during aging. KEY MESSAGES SMP30-deficient mice induced a shorter lifespan and redox changes. Overexpression of SMP30 prevented oxidative stress insults. The depletion of SMP30 increased redox-related PTK/PTP imbalance and PP1/PP2A inactivation. The depletion of SMP30 caused an elevation of NF-κB-responsive inflammatory markers. SMP30 may be a potent inhibitory protein against oxidative stress and chronic inflammation.
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Affiliation(s)
- Kyung Jin Jung
- Korea Institute of Toxicology, 141 Gajungro, Yuseong-gu, Daejeon, 305-343, Republic of Korea
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43
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Liu C, Wang F, Wang Y, Li Z. A versatile fluorescence turn-on assay for highly sensitive detection of tyrosine phosphatase activity. Chem Commun (Camb) 2014; 50:13983-6. [DOI: 10.1039/c4cc06793b] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Abstract
SIGNIFICANCE Protein tyrosine phosphatases (PTPs) play essential roles in controlling cell proliferation, differentiation, communication, and adhesion. The dysregulated activities of PTPs are involved in the pathogenesis of a number of human diseases such as cancer, diabetes, and autoimmune diseases. RECENT ADVANCES Many PTPs have emerged as potential new targets for novel drug discovery. PTP inhibitors have attracted much attention. Many PTP inhibitors have been developed. Some of them have been proven to be efficient in lowering blood glucose levels in vivo or inhibiting tumor xenograft growth. CRITICAL ISSUES Some metal ions and metal complexes potently inhibit PTPs. The metal atoms within metal complexes play an important role in PTP binding, while ligand structures influence the inhibitory potency and selectivity. Some metal complexes can penetrate the cell membrane and selectively bind to their targeting PTPs, enhancing the phosphorylation of the related substrates and influencing cellular metabolism. PTP inhibition is potentially involved in the pathophysiological and toxicological processes of metals and some PTPs may be cellular targets of certain metal-based therapeutic agents. FUTURE DIRECTIONS Investigating the structural basis of the interactions between metal complexes and PTPs would facilitate a comprehensive understanding of the structure-activity relationship and accelerate the development of promising metal-based drugs targeting specific PTPs.
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Affiliation(s)
- Liping Lu
- Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Institute of Molecular Science, Shanxi University , Taiyuan, People's Republic of China
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45
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Ríos P, Nunes-Xavier CE, Tabernero L, Köhn M, Pulido R. Dual-specificity phosphatases as molecular targets for inhibition in human disease. Antioxid Redox Signal 2014; 20:2251-73. [PMID: 24206177 DOI: 10.1089/ars.2013.5709] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
SIGNIFICANCE The dual-specificity phosphatases (DUSPs) constitute a heterogeneous group of cysteine-based protein tyrosine phosphatases, whose members exert a pivotal role in cell physiology by dephosphorylation of phosphoserine, phosphothreonine, and phosphotyrosine residues from proteins, as well as other non-proteinaceous substrates. RECENT ADVANCES A picture is emerging in which a selected group of DUSP enzymes display overexpression or hyperactivity that is associated with human disease, especially human cancer, making feasible targeted therapy approaches based on their inhibition. A panoply of molecular and functional studies on DUSPs have been performed in the previous years, and drug-discovery efforts are ongoing to develop specific and efficient DUSP enzyme inhibitors. This review summarizes the current status on inhibitory compounds targeting DUSPs that belong to the MAP kinase phosphatases-, small-sized atypical-, and phosphatases of regenerating liver subfamilies, whose inhibition could be beneficial for the prevention or mitigation of human disease. CRITICAL ISSUES Achieving specificity, potency, and bioavailability are the major challenges in the discovery of DUSP inhibitors for the clinics. Clinical validation of compounds or alternative inhibitory strategies of DUSP inhibition has yet to come. FUTURE DIRECTIONS Further work is required to understand the dual role of many DUSPs in human cancer, their function-structure properties, and to identify their physiologic substrates. This will help in the implementation of therapies based on DUSPs inhibition.
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Affiliation(s)
- Pablo Ríos
- 1 Genome Biology Unit, European Molecular Biology Laboratory , Heidelberg, Germany
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Abstract
SIGNIFICANCE Protein tyrosine phosphatases (PTPs) are important enzymes that are involved in the regulation of cellular signaling. Evidence accumulated over the years has indicated that PTPs present exciting opportunities for drug discovery against diseases such as diabetes, cancer, autoimmune diseases, and tuberculosis. However, the highly conserved and partially positive charge of the catalytic sites of PTPs is a major challenge in the development of potent and highly selective PTP inhibitors. RECENT ADVANCES Here, we examine the strategy of developing bidentate inhibitors for selective inhibition of PTPs. Bidentate inhibitors are small-molecular-weight compounds with the ability to bind to both the active site and a non-conserved secondary phosphate binding site. This secondary phosphate binding site was initially discovered in protein tyrosine phosphatase 1B (PTP1B), and, hence, most of the bidentate inhibitors reported in this review are PTP1B inhibitors. CRITICAL ISSUES Although bidentate inhibition is a good strategy for developing potent and selective inhibitors, the cell membrane permeability and pharmacokinetic properties of the inhibitors are also important for successful drug development. In this review, we will also summarize the various efforts made toward the development of phosphotyrosine (pTyr) mimetics for increasing cellular permeability. FUTURE DIRECTIONS Even though the secondary phosphate binding site was initially found in PTP1B, structural data have shown that a secondary binding site can also be found in other PTPs, albeit with varying degrees of accessibility. Along with improvements in pTyr mimetics, we believe that the future will see an increase in the number of orally bioavailable bidentate inhibitors against the various classes of PTPs.
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Affiliation(s)
- Joo-Leng Low
- 1 Institute of Chemical and Engineering Sciences , Agency for Science Technology and Research, Singapore, Singapore
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47
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Morales LD, Casillas Pavón EA, Shin JW, Garcia A, Capetillo M, Kim DJ, Lieman JH. Protein tyrosine phosphatases PTP-1B, SHP-2, and PTEN facilitate Rb/E2F-associated apoptotic signaling. PLoS One 2014; 9:e97104. [PMID: 24809452 PMCID: PMC4014576 DOI: 10.1371/journal.pone.0097104] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 04/15/2014] [Indexed: 11/20/2022] Open
Abstract
To maintain tissue homeostasis, apoptosis is functionally linked to the cell cycle through the retinoblastoma (Rb)/E2F pathway. When the Rb tumor suppressor protein is functionally inactivated, E2F1 elicits an apoptotic response through both intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) apoptotic pathways in order to eliminate hyperproliferative cells. Rb/E2F-associated apoptosis has been demonstrated to be associated with the loss of constitutive transcriptional repression by Rb/E2F complexes and mediated by caspase-8. Protein tyrosine phosphatases (PTPs) PTP-1B and SHP-2 have been previously shown to be directly activated by loss of Rb/E2F repression during Rb/E2F-associated apoptosis. In this current study, we demonstrate that the PTEN tumor suppressor is also directly activated by loss of Rb/E2F repression. We also demonstrate that PTP-1B, SHP-2, and PTEN play a functional role in Rb/E2F-associated apoptosis. Knockdown of PTP1B, SHP2, or PTEN expression with small interfering RNA (siRNA) in apoptotic cells increases cell viability and rescues cells from the Rb/E2F-associated apoptotic response. Furthermore, rescue from apoptosis coincides with inhibition of caspase-8 and caspase-3 cleavage (activation). Our results indicate PTP-1B, SHP-2, and PTEN all play a functional role in Rb/E2F-associated apoptotic signal transduction and provide further evidence that PTP-1B, SHP-2, and PTEN can contribute to tumor suppression through an Rb/E2F-associated mechanism.
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Affiliation(s)
- Liza D. Morales
- Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas, United States of America
| | - Edgar A. Casillas Pavón
- Department of Biology, University of Texas-Pan American, Edinburg, Texas, United States of America
| | - Jun Wan Shin
- Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas, United States of America
| | - Alexander Garcia
- Department of Biology, University of Texas-Pan American, Edinburg, Texas, United States of America
| | - Mario Capetillo
- Department of Biology, University of Texas-Pan American, Edinburg, Texas, United States of America
| | - Dae Joon Kim
- Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas, United States of America
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Jonathan H. Lieman
- Department of Biology, University of Texas-Pan American, Edinburg, Texas, United States of America
- Department of Biology, South Texas College, McAllen, Texas, United States of America
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48
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Huang TL, Mayence A, Vanden Eynde JJ. Some non-conventional biomolecular targets for diamidines. A short survey. Bioorg Med Chem 2014; 22:1983-92. [DOI: 10.1016/j.bmc.2014.02.049] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 02/19/2014] [Accepted: 02/24/2014] [Indexed: 12/24/2022]
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49
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Través PG, Pardo V, Pimentel-Santillana M, González-Rodríguez Á, Mojena M, Rico D, Montenegro Y, Calés C, Martín-Sanz P, Valverde AM, Boscá L. Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge. Cell Death Dis 2014; 5:e1125. [PMID: 24625984 PMCID: PMC3973223 DOI: 10.1038/cddis.2014.90] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/31/2014] [Accepted: 02/10/2014] [Indexed: 02/07/2023]
Abstract
Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In the present work, we have investigated the effect of PTP1B deficiency on the response of human and murine macrophages. Using in vitro and in vivo approaches in mice and silencing PTP1B in human macrophages with specific siRNAs, we have demonstrated that PTP1B deficiency increases the effects of pro-inflammatory stimuli in both human and rodent macrophages at the time that decreases the response to alternative stimulation. Moreover, the absence of PTP1B induces a loss of viability in resting macrophages and mainly after activation through the classic pathway. Analysis of early gene expression in macrophages treated with pro-inflammatory stimuli confirmed this exacerbated inflammatory response in PTP1B-deficient macrophages. Microarray analysis in samples from wild-type and PTP1B-deficient macrophages obtained after 24 h of pro-inflammatory stimulation showed an activation of the p53 pathway, including the excision base repair pathway and the insulin signaling pathway in the absence of PTP1B. In animal models of lipopolysaccharide (LPS) and D-galactosamine challenge as a way to reveal in vivo inflammatory responses, animals lacking PTP1B exhibited a higher rate of death. Moreover, these animals showed an enhanced response to irradiation, in agreement with the data obtained in the microarray analysis. In summary, these results indicate that, although inhibition of PTP1B has potential benefits for the treatment of diabetes, it accentuates pro-inflammatory responses compromising at least macrophage viability.
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MESH Headings
- Animals
- Cell Survival
- Cells, Cultured
- Disease Models, Animal
- Galactosamine
- Gene Expression Profiling/methods
- Humans
- Immunity, Innate
- Inflammation/chemically induced
- Inflammation/enzymology
- Inflammation/genetics
- Inflammation/immunology
- Inflammation/pathology
- Inflammation Mediators/metabolism
- Lipopolysaccharides
- Macrophage Activation
- Macrophages, Peritoneal/enzymology
- Macrophages, Peritoneal/immunology
- Macrophages, Peritoneal/pathology
- Male
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Oligonucleotide Array Sequence Analysis
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/deficiency
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism
- RNA Interference
- Signal Transduction
- Time Factors
- Transfection
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- P G Través
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - V Pardo
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain
| | - M Pimentel-Santillana
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - Á González-Rodríguez
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain
| | - M Mojena
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - D Rico
- Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), ISCIII, Madrid, Spain
| | - Y Montenegro
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - C Calés
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - P Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), ISCIII, Madrid, Spain
| | - A M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain
| | - L Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), ISCIII, Madrid, Spain
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Peng Q, Schork NJ. Utility of network integrity methods in therapeutic target identification. Front Genet 2014; 5:12. [PMID: 24550933 PMCID: PMC3909879 DOI: 10.3389/fgene.2014.00012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 01/13/2014] [Indexed: 01/05/2023] Open
Abstract
Analysis of the biological gene networks involved in a disease may lead to the identification of therapeutic targets. Such analysis requires exploring network properties, in particular the importance of individual network nodes (i.e., genes). There are many measures that consider the importance of nodes in a network and some may shed light on the biological significance and potential optimality of a gene or set of genes as therapeutic targets. This has been shown to be the case in cancer therapy. A dilemma exists, however, in finding the best therapeutic targets based on network analysis since the optimal targets should be nodes that are highly influential in, but not toxic to, the functioning of the entire network. In addition, cancer therapeutics targeting a single gene often result in relapse since compensatory, feedback and redundancy loops in the network may offset the activity associated with the targeted gene. Thus, multiple genes reflecting parallel functional cascades in a network should be targeted simultaneously, but require the identification of such targets. We propose a methodology that exploits centrality statistics characterizing the importance of nodes within a gene network that is constructed from the gene expression patterns in that network. We consider centrality measures based on both graph theory and spectral graph theory. We also consider the origins of a network topology, and show how different available representations yield different node importance results. We apply our techniques to tumor gene expression data and suggest that the identification of optimal therapeutic targets involving particular genes, pathways and sub-networks based on an analysis of the nodes in that network is possible and can facilitate individualized cancer treatments. The proposed methods also have the potential to identify candidate cancer therapeutic targets that are not thought to be oncogenes but nonetheless play important roles in the functioning of a cancer-related network or pathway.
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Affiliation(s)
- Qian Peng
- Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, CA, USA ; Scripps Genomic Medicine, The Scripps Translational Science Institute La Jolla, CA, USA
| | - Nicholas J Schork
- Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, CA, USA ; Scripps Genomic Medicine, The Scripps Translational Science Institute La Jolla, CA, USA
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