首页|Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

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For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor Venetoclax.The pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and immunity.The dysregulation of BAX is closely asso-ciated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart failure.In addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX modulators.This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX.Furthermore,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

ApoptosisPro-apoptotic protein BAXDynamic conformational activationSmall-molecule apoptosis modulators

Zhenwei Zhang、Linghui Hou、Dan Liu、Shenglin Luan、Min Huang、Linxiang Zhao

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Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China

China Resources Sanjiu Medical & Pharmaceutical Co.,Ltd.,Shenzhen 518000,China

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaLiaoning Revitalization Talents Program,ChinaNatural Science Foundation of Liaoning Province,ChinaGeneral Scientific Research Projects of Department of Education in Liaoning Province,ChinaGeneral Scientific Research Projects of Department of Education in Liaoning Province,ChinaExcellent Youth Talent Support Program of Shenyang Pharmaceutical University,China

8217368782204218XLYC19020892020-BS-155LJKQZ2021032LJKZ0930YQ202304

2024

10.1016/j.apsb.2024.02.010

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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