Targeted protein degradation in drug development: Recent advances and future challenges
药物开发中的靶向蛋白降解：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)
采用结构生物学、计算机模拟和实验验证相结合的方法，系统分析蛋白质结构和功能关系。通过分子对接、动力学模拟等技术预测药物-靶点相互作用。
实验结果 (Experimental Results)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
数据汇总 (Data Summary)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
结论 (Conclusions)
基于蛋白质的药物研发策略为创新药物开发提供了新方向。
实践意义 (Practical Significance)
对推动靶向药物研发和精准医疗发展具有重要科学价值。