The B-cell lymphoma-2 (BCL-2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL-2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small-molecules have been designed to modulate the protein–protein interactions between anti- and proapoptotic BCL-2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL-2 homology 3 (BH3) mimetics to target antiapoptotic BCL-2 proteins, thereby competitively releasing proapoptotic BCL-2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL-2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL-2-associated X protein (BAX) or BCL-2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL-2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.

中文翻译：

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十字准线中的 B 细胞淋巴瘤 2 家族蛋白：用于癌症治疗的小分子抑制剂和激活剂

B 细胞淋巴瘤 2 (BCL-2) 蛋白家族在细胞凋亡的调节中发挥着至关重要的作用，为其控制提供了双重机制。许多研究已经证实这些蛋白质的基因疾病与多种癌细胞类型的增殖之间存在密切关联。因此，针对 BCL-2 家族蛋白的药物的鉴定和开发已成为抗肿瘤治疗的一个重要领域。在过去的二十年里，一些小分子被设计来调节抗凋亡和促凋亡 BCL-2 蛋白之间的蛋白质相互作用，有效抑制体内肿瘤生长和转移。研究的主要焦点是开发 BCL-2 同源 3 (BH3) 模拟物来靶向抗凋亡 BCL-2 蛋白，从而竞争性释放促凋亡 BCL-2 蛋白并恢复受阻的内在凋亡程序。此外，对于促凋亡 BCL-2 蛋白，外源小分子已被探索通过直接与 BCL-2 相关 X 蛋白 (BAX) 或 BCL-2 同源拮抗剂/杀伤蛋白 (BAK) 等执行者蛋白相互作用来激活细胞凋亡。在这篇综合综述中，我们总结了过去几十年开发的 BCL-2 家族蛋白的抑制剂和激活剂（敏化剂），重点介绍了它们的发现、优化、临床前和临床状态，并提供了针对这些蛋白进行治疗的药物开发的总体情况目的。