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.

中文翻译：

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直接靶向 BAX 进行药物发现：治疗机遇和挑战

二十多年来，B 细胞淋巴瘤 2 (Bcl-2) 家族疗法的开发主要集中在抗凋亡蛋白上，从而产生了称为 BH3 模拟物的一流药物，特别是 Bcl-2 抑制剂 Venetoclax 。促凋亡蛋白 Bcl-2 相关 X 蛋白 (BAX) 作为线粒体调节细胞死亡的执行蛋白发挥着至关重要的作用，有助于机体发育、组织稳态和免疫。BAX 的失调与以病理细胞存活或死亡为特征的疾病的发生和进展密切相关，例如癌症、神经变性和心力衰竭。除了对 BAX 的生理调节进行深入研究外，通过生化筛选方法鉴定的小分子调节机制的研究也促进了 BAX 上功能性和潜在可药物结合位点的鉴定，以及各种全分子 BAX 调节剂。这篇综述介绍了阐明 BAX 的生理和药理学调节以及识别 BAX 上潜在的药物结合位点方面的最新进展。此外，它还强调了针对针对 BAX 不同结合表面或构象的小分子调节剂的结构和机制见解，为开发下一代细胞凋亡调节剂提供了一条有前途的途径，通过直接靶向 BAX 来治疗与细胞死亡失调相关的多种疾病。