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Meli R, Aksoy O, Vallet S, Slade D, Podar K. Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy. Expert Opin Ther Targets 2025; 29:101-115. [PMID: 40122131 DOI: 10.1080/14728222.2025.2482557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/26/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Transcription factors (TFs) are master regulators of cellular function and orchestrate diverse signaling pathways and processes. Acting as convergence points of signaling pathways, they integrate extracellular stimuli with intracellular responses to regulate cell functions. Dysregulation of TFs drives tumorigenesis including proliferation, drug resistance, and immune evasion of multiple myeloma (MM), the second most-common hematologic malignancy. AREAS COVERED The discovery that IMiDs are molecular glue degraders, which reprogram the E3-ligase cereblon (CRBN) to ubiquitinate and degrade IKZF1 and IKZF3, two otherwise un-druggable crucial TFs in MM, gave rise to the widespread interest in proximity-induced protein-degradation as an exciting novel therapeutic strategy. This review summarizes our up-to-date knowledge on the pre/clinical development of IMiD-related, more potent CRBN E3-Ligase Modulatory Drugs (CELMoDs), directed PROteolysis TArgeting Chimeras (PROTACs) and degronomids as well as on promising future avenues in the field of targeted protein-degradation (TPD). EXPERT OPINION TPD is an emerging field to treat cancer, including MM. CELMoDs are already reshaping the treatment landscape of MM. Preclinical data on PROTACs are promising. Nevertheless, a deeper understanding of TF biology as well as further advancements in screening methodologies and chemoproteomics are crucial to further spur the transformative potential of targeted TF degradation in MM.
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Affiliation(s)
- Rajeshwari Meli
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Osman Aksoy
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Sonia Vallet
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Division of Internal Medicine, University Hospital Krems, Krems an der Donau, Austria
| | - Dea Slade
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria
- Center for Medical Biochemistry, Medical University of Vienna, Vienna, Austria
| | - Klaus Podar
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Division of Internal Medicine, University Hospital Krems, Krems an der Donau, Austria
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Apprato G, Caron G, Deshmukh G, Garcia-Jimenez D, Haid RTU, Pike A, Reichel A, Rynn C, Donglu Z, Wittwer MB. Finding a needle in the haystack: ADME and pharmacokinetics/pharmacodynamics characterization and optimization toward orally available bifunctional protein degraders. Expert Opin Drug Discov 2025. [PMID: 39956925 DOI: 10.1080/17460441.2025.2467195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/17/2025] [Accepted: 02/11/2025] [Indexed: 02/18/2025]
Abstract
INTRODUCTION Degraders are an increasingly important sub-modality of small molecules as illustrated by an ever-expanding number of publications and clinical candidate molecules in human trials. Nevertheless, their preclinical optimization of ADME and PK/PD properties has remained challenging. Significant research efforts are being directed to elucidate underlying principles and to derive rational optimization strategies. AREAS COVERED In this review the authors summarize current best practices in terms of in vitro assays and in vivo experiments. Furthermore, the authors collate and comment on the current understanding of optimal physicochemical characteristics and their impact on absorption, distribution, metabolism and excretion properties including the current knowledge of Drug-Drug interactions. Finally, the authors describe the Pharmacokinetic prediction and Pharmacokinetic/Pharmacodynamic -concepts unique to degraders and how to best implement these in research projects. EXPERT OPINION Despite many recent advances in the field, continued research will further our understanding of rational design regarding degrader optimization. Machine-learning and computational approaches will become increasingly important once larger, more robust datasets become available. Furthermore, tissue-targeting approaches (particularly regarding the Central Nervous System will be increasingly studied to elucidate efficacious drug regimens that capitalize on the catalytic mode of action. Finally, additional specialized approaches (e.g. covalent degraders, LOVdegs) can enrich the field further and offer interesting alternative approaches.
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Affiliation(s)
- Giulia Apprato
- CASSMedChem, Molecular Biotechnology and Health Sciences Dept, University of Torino, Torino, Italy
| | - Giulia Caron
- CASSMedChem, Molecular Biotechnology and Health Sciences Dept, University of Torino, Torino, Italy
| | | | - Diego Garcia-Jimenez
- CASSMedChem, Molecular Biotechnology and Health Sciences Dept, University of Torino, Torino, Italy
| | - Robin Thomas Ulrich Haid
- Preclinical Modeling & Simulation, Pharma R&D, Bayer AG, Berlin, Germany
- Biopharmacy, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Andy Pike
- DMPK, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Andreas Reichel
- Preclinical Modeling & Simulation, Pharma R&D, Bayer AG, Berlin, Germany
| | - Caroline Rynn
- Roche Products Ltd, Hexagon Place, 6 Falcon Way, Welwyn Garden City, UK
| | | | - Matthias Beat Wittwer
- pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. 4070 Basel, Switzerland
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Zou ZF, Yang L, Nie HJ, Gao J, Lei SM, Lai Y, Zhang F, Wagner E, Yu HJ, Chen XH, Xu ZA. Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy. Acta Pharmacol Sin 2024; 45:1740-1751. [PMID: 38609561 PMCID: PMC11272941 DOI: 10.1038/s41401-024-01266-z] [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: 12/23/2023] [Accepted: 03/12/2024] [Indexed: 04/14/2024]
Abstract
Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.
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Affiliation(s)
- Zhi-Feng Zou
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China
- State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Lei Yang
- State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hui-Jun Nie
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jing Gao
- State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Shu-Min Lei
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yi Lai
- State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Fan Zhang
- Department of Chemistry, Fudan University, Shanghai, 20043, China
| | - Ernst Wagner
- Department of Pharmacy, Ludwig-Maximilians-Universität, 81377, München, Germany
| | - Hai-Jun Yu
- State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xiao-Hua Chen
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
| | - Zhi-Ai Xu
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
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Jiang Y, Lin Y, Tetlow AM, Pan R, Ji C, Kong XP, Congdon EE, Sigurdsson EM. Single-domain antibody-based protein degrader for synucleinopathies. Mol Neurodegener 2024; 19:44. [PMID: 38816762 PMCID: PMC11140919 DOI: 10.1186/s13024-024-00730-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/06/2024] [Indexed: 06/01/2024] Open
Abstract
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
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Affiliation(s)
- Yixiang Jiang
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Yan Lin
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Amber M Tetlow
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Ruimin Pan
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Changyi Ji
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Xiang-Peng Kong
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Erin E Congdon
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Einar M Sigurdsson
- Department of Neuroscience and Physiology, and Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA.
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA.
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Li D, Deng Y, Wen G, Wang L, Shi X, Chen S, Chen R. Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization. Int Immunopharmacol 2024; 132:111991. [PMID: 38581996 DOI: 10.1016/j.intimp.2024.111991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/06/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024]
Abstract
OBJECTIVES Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury. METHODS This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay. RESULTS In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages. CONCLUSION Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.
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Affiliation(s)
- Difei Li
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yao Deng
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Guanxi Wen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Lingwei Wang
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Xing Shi
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Shanze Chen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Rongchang Chen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
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Su J, Xiao Y, Wei L, Lei H, Sun F, Wang W, Yin J, Xiong R, Li S, Zhang P, Zhou Y, Wang X, Zheng J, Wang JZ. Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer's disease and related tauopathies. Sci Bull (Beijing) 2024; 69:1137-1152. [PMID: 38341350 DOI: 10.1016/j.scib.2024.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/06/2023] [Accepted: 01/08/2024] [Indexed: 02/12/2024]
Abstract
Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.
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Affiliation(s)
- Jingfen Su
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yue Xiao
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Linyu Wei
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China
| | - Huiyang Lei
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fei Sun
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Weixia Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jun Yin
- Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430030, China
| | - Rui Xiong
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shihong Li
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Pei Zhang
- The Core Facility and Technical Support, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430030, China
| | - Ying Zhou
- Research Center for Medicine and Structural Biology, Wuhan University, Wuhan 430030, China
| | - Xiaochuan Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Jie Zheng
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Beijing 100083, China.
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China.
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Wang S, Lei K, Lai HT, Liu T, Du L, Wu SY, Ye X, Chiang CM, Li M. Novel BRD4-p53 Inhibitor SDU-071 Suppresses Proliferation and Migration of MDA-MB-231 Triple-Negative Breast Cancer Cells. ACS Pharmacol Transl Sci 2024; 7:1178-1190. [PMID: 38633583 PMCID: PMC11019737 DOI: 10.1021/acsptsci.4c00057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 04/19/2024]
Abstract
A promising alternative for cancer treatment involves targeted inhibition of the epigenetic regulator bromodomain-containing protein 4 (BRD4); however, available BRD4 inhibitors are constrained by their potency, oral bioavailability, and cytotoxicity. Herein, to overcome the drawback of the translational BRD4 inhibitors, we describe a novel BRD4-p53 inhibitor, SDU-071, which suppresses BRD4 interaction with the p53 tumor suppressor and its biological activity in MDA-MB-231 triple-negative breast cancer (TNBC) cells in vitro and in vivo. This novel small-molecule BRD4-p53 inhibitor suppresses cell proliferation, migration, and invasion by downregulating the expression of BRD4-targeted genes, such as c-Myc and Mucin 5AC, and inducing cell cycle arrest and apoptosis, as demonstrated in cultured MDA-MB-231 TNBC cells. Its antitumor activity is illustrated in an orthotopic mouse xenograft mammary tumor model. Overall, our results show that SDU-071 is a viable option for potentially treating TNBC as a new BRD4-p53 inhibitor.
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Affiliation(s)
- Shumei Wang
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Kang Lei
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
- School
of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China
| | - Hsien-Tsung Lai
- Simmons
Comprehensive Cancer Center, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Tingting Liu
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Lupei Du
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Shwu-Yuan Wu
- Simmons
Comprehensive Cancer Center, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department
of Biochemistry, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Xiaohan Ye
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Cheng-Ming Chiang
- Simmons
Comprehensive Cancer Center, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department
of Biochemistry, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
- Department
of Pharmacology, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Minyong Li
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
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Xie H, Zhang C. Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin-Proteasome system. Eur J Med Chem 2024; 267:116168. [PMID: 38310686 DOI: 10.1016/j.ejmech.2024.116168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/11/2024] [Accepted: 01/21/2024] [Indexed: 02/06/2024]
Abstract
In eukaryotic cells, the ubiquitin-proteasome system (UPS) plays a crucial role in selectively breaking down specific proteins. The ability of the UPS to target proteins effectively and expedite their removal has significantly contributed to the evolution of UPS-based targeted protein degradation (TPD) strategies. In particular, proteolysis targeting chimeras (PROTACs) are an immensely promising tool due to their high efficiency, extensive target range, and negligible drug resistance. This breakthrough has overcome the limitations posed by traditionally "non-druggable" proteins. However, their high molecular weight and constrained solubility impede the delivery of PROTACs. Fortunately, the field of nanomedicine has experienced significant growth, enabling the delivery of PROTACs through nanoscale drug-delivery systems, which effectively improves the stability, solubility, drug distribution, tissue-specific accumulation, and stimulus-responsive release of PROTACs. This article reviews the mechanism of action attributed to PROTACs and their potential implications for clinical applications. Moreover, we present strategies involving nanoplatforms for the effective delivery of PROTACs and evaluate recent advances in targeting nanoplatforms to the UPS. Ultimately, an assessment is conducted to determine the feasibility of utilizing PROTACs and nanoplatforms for UPS-based TPD. The primary aim of this review is to provide innovative, reliable solutions to overcome the current challenges obstructing the effective use of PROTACs in the management of cancer, neurodegenerative diseases, and metabolic syndrome. Therefore, this is a promising technology for improving the treatment status of major diseases.
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Affiliation(s)
- Hanshu Xie
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Chao Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
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Li Y, Guo Y, Zhang K, Zhu R, Chen X, Zhang Z, Yang W. Cell Death Pathway Regulation by Functional Nanomedicines for Robust Antitumor Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306580. [PMID: 37984863 PMCID: PMC10797449 DOI: 10.1002/advs.202306580] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/16/2023] [Indexed: 11/22/2023]
Abstract
Cancer immunotherapy has become a mainstream cancer treatment over traditional therapeutic modes. Cancer cells can undergo programmed cell death including ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis which are find to have intrinsic relationships with host antitumor immune response. However, direct use of cell death inducers or regulators may bring about severe side effects that can also be rapidly excreted and degraded with low therapeutic efficacy. Nanomaterials are able to carry them for long circulation time, high tumor accumulation and controlled release to achieve satisfactory therapeutic effect. Nowadays, a large number of studies have focused on nanomedicines-based strategies through modulating cell death modalities to potentiate antitumor immunity. Herein, immune cell types and their function are first summarized, and state-of-the-art research progresses in nanomedicines mediated cell death pathways (e.g., ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis) with immune response provocation are highlighted. Subsequently, the conclusion and outlook of potential research focus are discussed.
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Affiliation(s)
- Yongjuan Li
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
- Medical Research CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan450001China
- The center of Infection and ImmunityAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450001China
| | - Yichen Guo
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
| | - Kaixin Zhang
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
| | - Rongrong Zhu
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, SurgeryChemical and Biomolecular Engineering, and Biomedical EngineeringYong Loo Lin School of Medicine and Faculty of EngineeringNational University of SingaporeSingapore119074Singapore
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117599Singapore
- Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117597Singapore
| | - Zhenzhong Zhang
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
| | - Weijing Yang
- School of Pharmaceutical SciencesHenan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhouHenan450001China
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10
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Wang C, Tian W, Song Z, Wang Q, Cao Y, Xiao J. Effects of solid lipid ratio in curcumin loaded emulsions on its gastrointestinal fate: Colloidal stability and mucus absorption efficiency. Food Res Int 2024; 175:113631. [PMID: 38128976 DOI: 10.1016/j.foodres.2023.113631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/17/2023] [Accepted: 10/21/2023] [Indexed: 12/23/2023]
Abstract
Emulsions offer a promising approach for enhancing the bioavailability of lipophilic active compounds when administered orally. Nonetheless, the impact of lipid matrix composition on the efficacy of penetration and bioavailability remains uncertain. This research investigated the effects of solid lipid ratio in emulsions on colloidal stability, mucus permeability, and bioavailability in vivo. To assess colloidal stability in the gastrointestinal tract (GIT), Turbiscan was employed. The results indicated that an elevated solid lipid ratio improved intestinal stability through the formation of aggregations that resisted pancreatic absorption, as confirmed by TEM. The absorption in various intestinal sections was tested using the Ussing Chamber model. Notably, emulsion with 0 % solid lipid (G0M10) exhibited the highest cumulative permeation across the duodenum (221.2 ± 21.19 ng), jejunum (713.1 ± 20.93 ng), and ileum (1056.3 ± 392.06 ng) due to its higher in vitro release rate (>60 %) and smaller particle size. The cumulative permeation decreased with increasing solid lipid ratio. CLSM revealed that emulsions with a solid lipid ratio exceeding 50 % exhibited poor mucus permeability within 15 min due to aggregation during the passage in the GIT. However, over an extended penetration time (30 min), higher permeability was observed, reaching approximately 30 μm. In vitro release studies indicated that a higher solid lipid ratio resulted in a reduced release rate of curcumin (<60 %) compared to G0M10 (66.9 ± 3.58 %). Correlation analysis unveiled a positive link between bioavailability and in vitro release rate, while a negative correlation emerged with the solid lipid ratio. This work underscores the significance of solid lipid ratios in emulsions for optimizing bioavailability through their influence on stability, permeability, and release of lipophilic compounds in the GIT.
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Affiliation(s)
- Chujing Wang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China
| | - Wenni Tian
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China
| | - Zengliu Song
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China
| | - Qun Wang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, Guangdong, PR China.
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11
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Lv S, Zhang J, Peng X, Liu H, Liu Y, Wei F. Ubiquitin signaling in pancreatic ductal adenocarcinoma. Front Mol Biosci 2023; 10:1304639. [PMID: 38174069 PMCID: PMC10761520 DOI: 10.3389/fmolb.2023.1304639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor of the digestive system, characterized by rapid progression and being prone to metastasis. Few effective treatment options are available for PDAC, and its 5-year survival rate is less than 9%. Many cell biological and signaling events are involved in the development of PDAC, among which protein post-translational modifications (PTMs), such as ubiquitination, play crucial roles. Catalyzed mostly by a three-enzyme cascade, ubiquitination induces changes in protein activity mainly by altering their stability in PDAC. Due to their role in substrate recognition, E3 ubiquitin ligases (E3s) dictate the outcome of the modification. Ubiquitination can be reversed by deubiquitylases (DUBs), which, in return, modified proteins to their native form. Dysregulation of E3s or DUBs that disrupt protein homeostasis is involved in PDAC. Moreover, the ubiquitination system has been exploited to develop therapeutic strategies, such as proteolysis-targeting chimeras (PROTACs). In this review, we summarize recent progress in our understanding of the role of ubiquitination in the development of PDAC and offer perspectives in the design of new therapies against this highly challenging disease.
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Affiliation(s)
- Shengnan Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xinyu Peng
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huan Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yan Liu
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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12
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Yang L, Jing Y, Xia X, Yin X. ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4. JOURNAL OF ONCOLOGY 2023; 2023:9904143. [PMID: 38130463 PMCID: PMC10735731 DOI: 10.1155/2023/9904143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 10/07/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023]
Abstract
Objective The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.
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Affiliation(s)
- Liu Yang
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Yue Jing
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Xia Xia
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Xiushan Yin
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
- Roc Rock Biotechnology (Shenzhen), Shenzhen 518118, China
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13
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Zou Q, Liu M, Liu K, Zhang Y, North BJ, Wang B. E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities. Cell Oncol (Dordr) 2023; 46:545-570. [PMID: 36745329 PMCID: PMC10910623 DOI: 10.1007/s13402-023-00777-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2023] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination. CONCLUSION In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine.
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Affiliation(s)
- Qiang Zou
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, People's Republic of China
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Meng Liu
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, People's Republic of China
| | - Kewei Liu
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Yi Zhang
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, People's Republic of China.
| | - Brian J North
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, 68178, USA.
| | - Bin Wang
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People's Republic of China.
- Jinfeng Laboratory, Chongqing, 401329, People's Republic of China.
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14
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Sobhia ME, Kumar H, Kumari S. Bifunctional robots inducing targeted protein degradation. Eur J Med Chem 2023; 255:115384. [PMID: 37119667 DOI: 10.1016/j.ejmech.2023.115384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 05/01/2023]
Abstract
The gaining importance of Targeted Protein Degradation (TPD) and PROTACs (PROteolysis-TArgeting Chimeras) have drawn the scientific community's attention. PROTACs are considered bifunctional robots owing to their avidity for the protein of interest (POI) and E3-ligase, which induce the ubiquitination of POI. These molecules are based on event-driven pharmacology and are applicable in different conditions such as oncology, antiviral, neurodegenerative disease, acne etc., offering tremendous scope to researchers. In this review, primarily, we attempted to compile the recent works available in the literature on PROTACs for various targeted proteins. We summarized the design and development strategies with a focus on molecular information of protein residues and linker design. Rationalization of the ternary complex formation using Artificial Intelligence including machine & deep learning models and traditionally followed computational tools are also included in this study. Moreover, details describing the optimization of PROTACs chemistry and pharmacokinetic properties are added. Advanced PROTAC designs and targeting complex proteins, is summed up to cover the wide spectrum.
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Affiliation(s)
- M Elizabeth Sobhia
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector - 67, S. A. S. Nagar, Mohali, Punjab, 160062, India.
| | - Harish Kumar
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector - 67, S. A. S. Nagar, Mohali, Punjab, 160062, India
| | - Sonia Kumari
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector - 67, S. A. S. Nagar, Mohali, Punjab, 160062, India
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15
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Li S, Chen T, Liu J, Zhang H, Li J, Wang Z, Shang G. PROTACs: Novel tools for improving immunotherapy in cancer. Cancer Lett 2023; 560:216128. [PMID: 36933781 DOI: 10.1016/j.canlet.2023.216128] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023]
Abstract
Posttranslational modifications (PTMs), such as phosphorylation, methylation, ubiquitination, and acetylation, are important in governing protein expression levels. Proteolysis targeting chimeras (PROTACs) are novel structures designed to target a protein of interest (POI) for ubiquitination and degradation, leading to the selective reduction in the expression levels of the POI. PROTACs have exhibited great promise due to their ability to target undruggable proteins, including several transcription factors. Recently, PROTACs have been characterized to improve anticancer immunotherapy via the regulation of specific proteins. In this review, we describe how the PROTACs target several molecules, including HDAC6, IDO1, EGFR, FoxM1, PD-L1, SHP2, HPK1, BCL-xL, BET proteins, NAMPT, and COX-1/2, to regulate immunotherapy in human cancers. PROTACs may provide potential treatment benefits by enhancing immunotherapy in cancer patients.
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Affiliation(s)
- Shizhe Li
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
| | - Ting Chen
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
| | - Jinxin Liu
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
| | - He Zhang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
| | - Jiatong Li
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
| | - Zhiwei Wang
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Anhui, 233030, China; The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
| | - Guanning Shang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
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16
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PROTACs: Promising approach for anticancer therapy. Cancer Lett 2023; 556:216065. [PMID: 36642326 DOI: 10.1016/j.canlet.2023.216065] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/11/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
Proteolysis-targeting chimeras (PROTACs) are being developed as an effective method for degrading cancer-related proteins by modifying the endogenous ubiquitin-proteasome system. To investigate the dynamics between an E3 ligase and target protein, researchers have developed a wide variety of bifunctional PROTACs by combining small molecule ligands. These PROTACs employ numerous ligands, some of which are reversible, some of which are irreversible, some attach to orthosteric sites, while others bind to allosteric sites. Some are agonists, while others are antagonists, and the target protein may be activated in either a positive or negative manner. A variety of targeted ligand approaches can be used to enhance PROTAC properties, including tumor selectivity and drug delivery, and to overcome drug resistance. The processes and behaviors of small molecule-based PROTACs and targeted proteolysis approaches as anticancer therapeutic molecules have been introduced in this mini-review.
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17
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Moon Y, Jeon SI, Shim MK, Kim K. Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy. Pharmaceutics 2023; 15:411. [PMID: 36839734 PMCID: PMC9965039 DOI: 10.3390/pharmaceutics15020411] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/20/2023] [Accepted: 01/22/2023] [Indexed: 01/28/2023] Open
Abstract
Proteolysis-targeting chimeras (PROTACs) are rapidly emerging as a potential therapeutic strategy for cancer therapy by inducing the degradation of tumor-overexpressing oncogenic proteins. They can specifically catalyze the degradation of target oncogenic proteins by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway. Since their mode of action is universal, irreversible, recyclable, long-lasting, and applicable to 'undruggable' proteins, PROTACs are gradually replacing the role of conventional small molecular inhibitors. Moreover, their application areas are being expanded to cancer immunotherapy as various types of oncogenic proteins that are involved in immunosuppressive tumor microenvironments. However, poor water solubility and low cell permeability considerably restrict the pharmacokinetic (PK) property, which necessitates the use of appropriate delivery systems for cancer immunotherapy. In this review, the general characteristics, developmental status, and PK of PROTACs are first briefly covered. Next, recent studies on the application of various types of passive or active targeting delivery systems for PROTACs are introduced, and their effects on the PK and tumor-targeting ability of PROTACs are described. Finally, recent drug delivery systems of PROTACs for cancer immunotherapy are summarized. The adoption of an adequate delivery system for PROTAC is expected to accelerate the clinical translation of PROTACs, as well as improve its efficacy for cancer therapy.
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Affiliation(s)
- Yujeong Moon
- Department of Bioengineering, Korea University, Seoul 02841, Republic of Korea
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Seong Ik Jeon
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Woman’s University, Seoul 03760, Republic of Korea
| | - Man Kyu Shim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Kwangmeyung Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Woman’s University, Seoul 03760, Republic of Korea
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18
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Liu X, Wang A, Shi Y, Dai M, Liu M, Cai HB. PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities. Molecules 2023; 28:molecules28031217. [PMID: 36770884 PMCID: PMC9919707 DOI: 10.3390/molecules28031217] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/24/2022] [Accepted: 01/06/2023] [Indexed: 01/28/2023] Open
Abstract
The epigenetic regulation of gene functions has been proven to be strongly associated with the development and progression of cancer. Reprogramming the cancer epigenome landscape is one of the most promising target therapies in both treatments and in reversing drug resistance. Proteolytic targeted chimeras (PROTACs) are an emerging therapeutic modality for selective degradation via the native ubiquitin-proteasome system. Rapid advances in PROTACs have facilitated the exploration of targeting epigenetic proteins, a lot of PROTAC degraders have already been designed in the field of epigenetic cancer therapy, and PROTACs targeting epigenetic proteins can better exploit target druggability and improve the mechanistic understanding of the epigenetic regulation of cancer. Thus, this review focuses on the progress made in the development of PROTAC degraders and PROTAC drugs targeting epigenetics in cancer and discusses challenges and future opportunities for the field.
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Affiliation(s)
- Xuelian Liu
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Anjin Wang
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Yuying Shi
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Mengyuan Dai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Cancer Clinical Study Center, Wuhan 430071, China
- Correspondence: (M.D.); (H.-B.C.)
| | - Miao Liu
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Hong-Bing Cai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Cancer Clinical Study Center, Wuhan 430071, China
- Correspondence: (M.D.); (H.-B.C.)
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19
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Zhao HY, Xin M, Zhang SQ. Progress of small molecules for targeted protein degradation: PROTACs and other technologies. Drug Dev Res 2023; 84:337-394. [PMID: 36606428 DOI: 10.1002/ddr.22026] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 12/01/2022] [Accepted: 12/17/2022] [Indexed: 01/07/2023]
Abstract
Recent years have witnessed the rapid development of targeted protein degradation (TPD), especially proteolysis targeting chimeras. These degraders have manifested many advantages over small molecule inhibitors. To date, a huge number of degraders have been excavated against over 70 disease-related targets. In particular, degraders against estrogen receptor and androgen receptor have crowded into phase II clinical trial. TPD technologies largely expand the scope of druggable targets, and provide powerful tools for addressing intractable problems that can not be tackled by traditional small molecule inhibitors. In this review, we mainly focus on the structures and biological activities of small molecule degraders as well as the elucidation of mechanisms of emerging TPD technologies. We also propose the challenges that exist in the TPD field at present.
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Affiliation(s)
- Hong-Yi Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Minhang Xin
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
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20
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Saraswat AL, Vartak R, Hegazy R, Patel A, Patel K. Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs). Drug Discov Today 2023; 28:103387. [PMID: 36184017 DOI: 10.1016/j.drudis.2022.103387] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/21/2022] [Accepted: 09/26/2022] [Indexed: 02/02/2023]
Abstract
Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the treatment of intractable diseases. However, PROTACs are poorly soluble and permeable bulky molecules facing several bioavailability challenges irrespective of the route of administration. Our review lays out crucial challenges in the delivery of target protein degraders and nanoformulation approaches to overcome physicochemical and biological hurdles that can aid in transporting these target-protein degraders to the disease site. We have elaborated on the current formulation approaches and further highlighted the prospective delivery strategies that could be probed for disease-specific targeted delivery of PROTACs.
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Affiliation(s)
- Aishwarya L Saraswat
- College of Pharmacy and Health Sciences, St John's University, Queens, NY 11439, USA
| | - Richa Vartak
- College of Pharmacy and Health Sciences, St John's University, Queens, NY 11439, USA
| | - Rehab Hegazy
- College of Pharmacy and Health Sciences, St John's University, Queens, NY 11439, USA; Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Akanksha Patel
- College of Pharmacy and Health Sciences, St John's University, Queens, NY 11439, USA
| | - Ketan Patel
- College of Pharmacy and Health Sciences, St John's University, Queens, NY 11439, USA.
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21
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He Y, Zan X, Miao J, Wang B, Wu Y, Shen Y, Chen X, Gou H, Zheng S, Huang N, Cheng Y, Ju Y, Fu X, Qian Z, Zhou P, Liu J, Gao X. Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles. Mater Today Bio 2022; 16:100423. [PMID: 36157053 PMCID: PMC9489811 DOI: 10.1016/j.mtbio.2022.100423] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 12/03/2022]
Abstract
Current treatment of glioma is hampered due to the physical blood-brain barrier (BBB) and the resistance to traditional chemotherapeutic agents. Herein, we proposed a combined treatment strategy based on Cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfk) peptides-modified nanoparticle named cRGD-P in a self-assembly method for the co-delivery of doxorubicin (DOX) and BRD4 PROTAC degrader ARV-825 (ARV). Molecular dynamics simulations showed that cRGD-P could change its conformation to provide interaction sites for perfectly co-loading DOX and ARV. The cRGD-P/ARV-DOX exhibited an average size of 39.95 nm and a zeta potential of −0.25 mV. Increased expression of BRD4 in glioma cells was observed after being stimulated by cRGD-P/DOX, confirming one of the possible mechanisms of DOX resistance and the synergistic tumor inhibition effect of BRD4 degrading ARV combined with DOX. In the study, the combination of DOX and ARV in the cRGD-P nanoparticle system exhibited synergistic suppression of tumor growth in glioma cells on account of cell cycle arrest in the G2/M phase and the activation of tumor cells apoptosis-related pathways including triggering caspase cascade and downregulating Bcl-2 as well as upregulating Bax. The cRGD-P/ARV-DOX system could effectively suppress the heterotopic and orthotopic growth of glioma by increasing tumor apoptosis, inhibiting tumor proliferation, and decreasing tumor angiogenesis in vivo. Therefore, the cRGD-modified nanoparticle to co-deliver DOX and ARV provides a potential platform for exploiting a more effective and safer combination therapy for glioma.
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Affiliation(s)
- Yihong He
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.,Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China
| | - Xin Zan
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Junming Miao
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Bilan Wang
- West China Second University Hospital of Sichuan University, Chengdu, 610041, PR China
| | - Yin Wu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yangmei Shen
- West China Second University Hospital of Sichuan University, Chengdu, 610041, PR China
| | - Xinchuan Chen
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Hongfeng Gou
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Songping Zheng
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Ning Huang
- Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China
| | - Yongzhong Cheng
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yan Ju
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xianghui Fu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Zhiyong Qian
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Peizhi Zhou
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Jiagang Liu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xiang Gao
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
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22
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Shi W, Feng Z, Chi F, Zhou J, Qiu Q, Jiang Y, Chen S, Zhong Y, Jia H, Huang W, Qian H. Structure-based discovery of receptor tyrosine kinase AXL degraders with excellent anti-tumor activity by selectively degrading AXL and inducing methuosis. Eur J Med Chem 2022; 234:114253. [DOI: 10.1016/j.ejmech.2022.114253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 11/04/2022]
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Juan A, del Mar Noblejas-López M, Arenas-Moreira M, Alonso-Moreno C, Ocaña A. Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles. Front Cell Dev Biol 2022; 9:805336. [PMID: 35186955 PMCID: PMC8851355 DOI: 10.3389/fcell.2021.805336] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/27/2021] [Indexed: 11/13/2022] Open
Abstract
Classical targeting in cancer focuses on the development of chemical structures able to bind to protein pockets with enzymatic activity. Some of these molecules are designed to bind the ATP side of the kinase domain avoiding protein activation and the subsequent oncogenic activity. A further improvement of these agents relies on the generation of non-allosteric inhibitors that once bound are able to limit the kinase function by producing a conformational change at the protein and, therefore, augmenting the antitumoural potency. Unfortunately, not all oncogenic proteins have enzymatic activity and cannot be chemically targeted with these types of molecular entities. Very recently, exploiting the protein degradation pathway through the ubiquitination and subsequent proteasomal degradation of key target proteins has gained momentum. With this approach, non-enzymatic proteins such as Transcription Factors can be degraded. In this regard, we provide an overview of current applications of the PROteolysis TArgeting Chimeras (PROTACs) compounds for the treatment of solid tumours and ways to overcome their limitations for clinical development. Among the different constraints for their development, improvements in bioavailability and safety, due to an optimized delivery, seem to be relevant. In this context, it is anticipated that those targeting pan-essential genes will have a narrow therapeutic index. In this article, we review the advantages and disadvantages of the potential use of drug delivery systems to improve the activity and safety of PROTACs.
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Affiliation(s)
- Alberto Juan
- Unidad NanoCRIB, Centro Regional de Investigaciones Biomédicas, Albacete, Spain
| | - María del Mar Noblejas-López
- Oncología Traslacional, Centro Regional de Investigaciones Biomédicas, Albacete, Spain
- Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, Oncología Traslacional, Albacete, Spain
| | | | - Carlos Alonso-Moreno
- Unidad NanoCRIB, Centro Regional de Investigaciones Biomédicas, Albacete, Spain
- Facultad de Farmacia de Albacete Universidad de Castilla-La Mancha, Albacete, Spain
| | - Alberto Ocaña
- Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, Oncología Traslacional, Albacete, Spain
- Experimental Therapeutics Unit, Hospital Clínico San Carlos, IdISSC and CIBERONC, Madrid, Spain
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24
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Yang T, Hu Y, Miao J, Chen J, Liu J, Cheng Y, Gao X. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization. Acta Pharm Sin B 2022; 12:2658-2671. [PMID: 35755286 PMCID: PMC9214068 DOI: 10.1016/j.apsb.2022.02.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/18/2022] [Accepted: 01/29/2022] [Indexed: 02/06/2023] Open
Abstract
Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood‒brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.
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Affiliation(s)
- Tingting Yang
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yuzhu Hu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
- Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Junming Miao
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Jing Chen
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Jiagang Liu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yongzhong Cheng
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Xiang Gao
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
- Corresponding author. Tel.: +86 28 85422136, fax +86 28 85502796.
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25
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Sun HY, Du ST, Li YY, Deng GT, Zeng FR. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:75-89. [PMID: 35116104 PMCID: PMC8790409 DOI: 10.4251/wjgo.v14.i1.75] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/11/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
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Affiliation(s)
- Hui-Yan Sun
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Song-Tao Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ya-Yun Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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26
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Liao X, Qian X, Zhang Z, Tao Y, Li Z, Zhang Q, Liang H, Li X, Xie Y, Zhuo R, Chen Y, Jiang Y, Cao H, Niu J, Xue C, Ni J, Pan J, Cui D. ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways. Front Oncol 2021; 11:753119. [PMID: 34733788 PMCID: PMC8559897 DOI: 10.3389/fonc.2021.753119] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/27/2021] [Indexed: 01/20/2023] Open
Abstract
Objective Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood. Methods Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model. Results The messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo. Conclusions High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
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Affiliation(s)
- Xinmei Liao
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoqing Qian
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zimu Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanfang Tao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Zhiheng Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Qian Zhang
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Liang
- Institute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, China
| | - Xiaolu Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yi Xie
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Ran Zhuo
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanling Chen
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - You Jiang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Haibo Cao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Jiaqi Niu
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Cuili Xue
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Ni
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Daxiang Cui
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Institute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, China
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27
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Kim HK, Seol JE, Ahn SW, Jeon S, Park CS, Han J. Cereblon: promise and challenges for combating human diseases. Pflugers Arch 2021; 473:1695-1711. [PMID: 34553266 DOI: 10.1007/s00424-021-02624-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 12/18/2022]
Abstract
Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. As new endogenous targets of CRBN have been identified over the past decade, the physiological and pathological functions of CRBN and its potential as a therapeutic target in various diseases have greatly expanded. For this purpose, in this review article, we introduce the basic principle of the ubiquitin-proteasome system, the regulation of physiological/pathological functions related to the endogenous substrate of CRBN, and the discovery of immunomodulatory imide drug-mediated neo-substrates of CRBN. In addition, the development of CRBN-based proteolysis-targeting chimeras, which has been actively researched recently, and strategies for developing therapeutic agents using them are introduced. These recent updates on CRBN will be useful in the establishment of strategies for disease treatment and utilization of CRBNs in biomedical engineering and clinical medicine.
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Affiliation(s)
- Hyoung Kyu Kim
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea
| | - Jung Eun Seol
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea
- Department of Dermatology, Inje University Busan Paik Hospital, Inje University, 47392, Busan, Korea
| | - Sang Woo Ahn
- Department of Dermatology, Inje University Busan Paik Hospital, Inje University, 47392, Busan, Korea
| | - Seungje Jeon
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Chul-Seung Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Jin Han
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea.
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28
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Lin J, Jin J, Shen Y, Zhang L, Gong G, Bian H, Chen H, Nagle DG, Wu Y, Zhang W, Luan X. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics 2021; 11:8337-8349. [PMID: 34373745 PMCID: PMC8344007 DOI: 10.7150/thno.62686] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/03/2021] [Indexed: 12/23/2022] Open
Abstract
Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
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Affiliation(s)
- Jiayi Lin
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jinmei Jin
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yiwen Shen
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lijun Zhang
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Gang Gong
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huiting Bian
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongzhuan Chen
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dale G. Nagle
- Department of Biomolecular Sciences and Research of Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA
| | - Ye Wu
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Weidong Zhang
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- School of Pharmacy, Second Military Medical University, Shanghai, 201203, China
| | - Xin Luan
- Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes. Cancer Cell Int 2021; 21:230. [PMID: 33888130 PMCID: PMC8061034 DOI: 10.1186/s12935-021-01908-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 04/07/2021] [Indexed: 12/16/2022] Open
Abstract
Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-01908-w.
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Alabi SB, Crews CM. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J Biol Chem 2021; 296:100647. [PMID: 33839157 PMCID: PMC8131913 DOI: 10.1016/j.jbc.2021.100647] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.
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Affiliation(s)
- Shanique B Alabi
- Department of Pharmacology, Yale University, New Haven, Connecticut, USA
| | - Craig M Crews
- Department of Pharmacology, Yale University, New Haven, Connecticut, USA; Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA; Department of Chemistry, Yale University, New Haven, Connecticut, USA.
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Mukherjee K. The 'What, Why, Where and How' of Delivering a Drug. Trends Pharmacol Sci 2020; 41:679-680. [PMID: 32946771 PMCID: PMC7497775 DOI: 10.1016/j.tips.2020.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Kusumika Mukherjee
- Trends in Pharmacological Sciences, Cell Press, 50 Hampshire Street, Cambridge, MA 02139, USA.
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