Apoptosis is a form of programmed cell death that is regulated by the balance between prosurvival and proapoptotic BCL-2 protein family members. Evasion of apoptosis is a hallmark of cancer that arises when this balance is tipped in favour of survival. One form of anticancer therapeutic, termed ‘BH3-mimetic drugs’, has been developed to directly activate the apoptosis machinery in malignant cells. These drugs bind to and inhibit specific prosurvival BCL-2 family proteins, thereby mimicking their interaction with the BH3 domains of proapoptotic BCL-2 family proteins. The BCL-2-specific inhibitor venetoclax is approved by the US Food and Drug Administration and many regulatory authorities worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. BH3-mimetic drugs targeting other BCL-2 prosurvival proteins have been tested in preclinical models of cancer, and drugs targeting MCL-1 or BCL-X_L have advanced into phase I clinical trials for certain cancers. As with all therapeutics, efficacy and tolerability need to be carefully balanced to achieve a therapeutic window whereby there is significant anticancer activity with an acceptable safety profile. In this Review, we outline the current state of BH3-mimetic drugs targeting various prosurvival BCL-2 family proteins and discuss emerging data regarding primary and acquired resistance to these agents and approaches that may overcome this. We highlight issues that need to be addressed to further advance the clinical application of BH3-mimetic drugs, both alone and in combination with additional anticancer agents (for example, standard chemotherapeutic drugs or inhibitors of oncogenic kinases), for improved responses in patients with cancer.

细胞凋亡是一种程序性细胞死亡形式，受促存活和促凋亡 BCL-2 蛋白家族成员之间的平衡调节。逃避细胞凋亡是癌症的一个标志，当这种平衡向有利于生存的方向倾斜时就会出现。一种称为“BH3 模拟药物”的抗癌疗法已被开发出来，可直接激活恶性细胞的细胞凋亡机制。这些药物结合并抑制特定的促存活 BCL-2 家族蛋白，从而模拟它们与促凋亡 BCL-2 家族蛋白的 BH3 结构域的相互作用。BCL-2特异性抑制剂venetoclax被美国食品药品监督管理局和全球许多监管机构批准用于治疗慢性淋巴细胞白血病和急性髓性白血病。_L已进入针对某些癌症的 I 期临床试验。与所有疗法一样，需要仔细平衡疗效和耐受性，以实现治疗窗，从而具有显着的抗癌活性和可接受的安全性。在这篇综述中，我们概述了针对各种促生存 BCL-2 家族蛋白的 BH3 模拟药物的现状，并讨论了有关对这些药物的原发性和获得性耐药性的新数据以及可能克服这一问题的方法。我们强调需要解决的问题，以进一步推进 BH3 模拟药物的临床应用，无论是单独使用还是与其他抗癌药物（例如，标准化疗药物或致癌激酶抑制剂）联合使用，以改善癌症患者的反应.