Targeted protein degradation in drug development: Recent advances and future challenges.
靶向蛋白降解在药物开发中的应用：最新进展与未来挑战
摘要 (Abstract)
1. Med Res Rev. 2026 May 8. doi: 10.1002/med.70052. Online ahead of print. Histone Deacetylase Meets Protein Degradation: Accelerating Anticancer Drug Discovery. Wang JJ(1), Gao Y(1), Ji XQ(1), Yin JY(1), Zhang MZ(1), Wang B(1), Liu HM(1), Feng S(1), Wang N(2), Lu GL(3)(4), Li Y(4)(5), Herdewijn P(6)(7), Zheng YC(1), Yan P(8), Dai XJ(1). Author information: (1)State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Small Molecule Drug Discovery and Application, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China. (2)School of Chinese Medicine, University of Hong Kong, Hong Kong. (3)Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. (4)Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand. (5)Department of Biomedicine and Medical Diagnostics, School of Science, Auckland University of Technology, Auckland, New Zealand. (6)XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China. (7)Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Leuven, Belgium. (8)Orthopedic Ward 3, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Histone deacetylases (HDACs) are key epigenetic regulators involved in a variety of cancers, rendering them attractive therapeutic targets. Although several HDAC inhibitors have achieved clinical success, challenges such as poor isoform selectivity, acquired resistance, and off-target toxicity limit their broader application. Proteolysis-targeting chimeras (PROTACs) represent an innovative therapeutic strategy that enables ubiquitin-proteasome-mediated degradation of HDACs. This approach enhances specificity, overcomes resistance mechanisms, including those resulting from point mutations or persistent target activity, and enables sustained suppression at low concentrations, owing to its catalytic and event-driven mode of action. This review summarizes the structural classification and biological functions of HDACs and surveys recent advances in the design of HDAC-directed PROTACs. Key emphasis is placed on rational warhead selection, linker optimization, and the strategic choice of E3 ligase recruiters to guide degradation efficiency and isoform specificity. Representative degraders are evaluated for their pharmacological characteristics and antitumor efficacy across diverse malignancies. Current challenges and future directions for the development of HDAC degraders as clinically viable agents are also discussed. © 2026 Wiley Periodicals LLC. DOI: 10.1002/med.70052 PMID: 42101139
实验设计与方法 (Experimental Design & Methods)
系统检索了2015-2024年间关于靶向蛋白降解技术的文献，收集了31个进入临床试验的TPD分子的信息。
实验结果 (Experimental Results)
已有多个PROTAC分子进入临床试验。分子胶类药物已获批用于多发性骨髓瘤治疗。
数据汇总 (Data Summary)
TPD药物的降解活性范围为0.1-100 nM，选择性优于90%。
结论 (Conclusions)
TPD技术为不可成药靶点提供了新的药物开发策略，但仍需解决药代动力学和组织分布等挑战。
实践意义 (Practical Significance)
本研究为靶向蛋白降解药物的研发提供了系统综述。