Loading…

Directly targeting BAX for drug discovery: Therapeutic opportunities and challenges

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) pl...

Full description

Saved in:
Bibliographic Details
Published in:Acta pharmaceutica Sinica. B 2024-06, Vol.14 (6), p.2378-2401
Main Authors: Zhang, Zhenwei, Hou, Linghui, Liu, Dan, Luan, Shenglin, Huang, Min, Zhao, Linxiang
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 associated 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. The elucidation of the physiologic and pharmacologic regulatory mechanisms of BAX and characterization of potential druggable binding sites offer an innovative avenue for developing next-generation apoptosis modulators to treat a wide range of diseases in the context of dysregulated cell death by directly targeting BAX. [Display omitted]
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2024.02.010