抗凋亡的BCL-2家族蛋白质，如BCL-2，BCL-XL和MCL-1，是优秀的癌症治疗靶点。2016年BCL-2选择性抑制剂威尼托克赛获得FDA批准，验证了利用BH3拟态小分子抑制剂靶向这些蛋白质的策略。本综述概述了覆盖2016年至2021年的抗凋亡BCL-2蛋白的抑制剂和PROTAC的专利文献。自威尼托克赛获得FDA批准以来，人们已经做出了巨大的努力，以开发具有改进药物性能的类似物。这些活动可能会在未来几年产生新的药物。关于MCL-1抑制剂的进展也取得了重大进展，多种化合物进入了临床试验。然而，MCL-1抑制可能会对正常组织，尤其是心脏，产生靶向毒性。BCL-XL抑制剂存在类似问题，会导致对靶向血小板的毒性。为了克服这个问题，采用了几种策略，包括伏特加，树枝状分子药物递送，抗体药物结合物（ADC）和蛋白酶解靶向嵌合体（PROTAC）；令人惊讶的是，每种方法都导致了一个药物候选进入临床试验。我们预想ADC和PROTAC等技术也可以被用于提高MCL-1抑制剂的治疗指数。

The anti-apoptotic BCL-2 family proteins, such as BCL-2, BCL-XL, and MCL-1, are excellent cancer therapeutic targets. The FDA approval of BCL-2 selective inhibitor venetoclax in 2016 validated the strategy of targeting these proteins with BH3 mimetic small molecule inhibitors.This review provides an overview of the patent literature between 2016 and 2021 covering inhibitors and PROTACs of the anti-apoptotic BCL-2 proteins.Since the FDA approval of venetoclax, tremendous efforts have been made to develop its analogues with improved drug properties. These activities will likely result in new drugs in coming years. Significant progress on MCL-1 inhibitors has also been made, with multiple compounds entering clinical trials. However, MCL-1 inhibition could cause on-target toxicity to normal tissues especially the heart. Similar issue exists with BCL-XL inhibitors, which cause on-target platelet toxicity. To overcome this issue, several strategies have been applied, including prodrug, dendrimer-based drug delivery, antibody-drug conjugate (ADC), and proteolysis targeting chimera (PROTAC); and amazingly, each of these approaches has resulted in a drug candidate entering clinical trials. We envision technologies like ADC and PROTAC could also be utilized to increase the therapeutic index of MCL-1 inhibitors.