AbbVie, Inc., North Chicago, Illinois.
Genentech, Inc., South San Francisco, California.
Cancer Discov. 2017 Dec;7(12):1376-1393. doi: 10.1158/2159-8290.CD-17-0797. Epub 2017 Nov 16.
Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax. Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors.
自细胞凋亡被发现为一种程序化细胞死亡形式以来，靶向细胞凋亡途径诱导癌细胞死亡一直是癌症治疗的首要目标。经过几十年的努力，药物发现科学家成功地生成了抗凋亡 BCL2 家族蛋白的小分子抑制剂。创新的药物化学和基于结构的药物设计，加上对 BCL2 生物学的深入理解，对于 BH3 模拟物（如 BCL2 选择性抑制剂 venetoclax）的开发至关重要。我们回顾了一些加深我们对 BCL2 生物学理解并促进 venetoclax 临床开发的临床前研究。对程序性细胞死亡途径的基础研究为凋亡诱导剂（如 venetoclax）的发现铺平了道路，venetoclax 是一种 BCL2 选择性抑制剂，最近已获得美国食品药品监督管理局和欧洲药品管理局的批准。迄今为止，旨在确定 BCL2 依赖性肿瘤类型的临床前研究已在临床上取得了良好的效果，并且可能会继续为 venetoclax 和其他 BCL2 家族抑制剂的临床开发提供信息。
