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.

Significance: 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. Cancer Discov; 7(12); 1376–93. ©2017 AACR.

自从发现凋亡是程序性细胞死亡的一种形式以来，靶向凋亡途径以诱导癌细胞死亡一直是癌症治疗的高度优先目标。经过数十年的努力，药物发现科学家成功地产生了抗凋亡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生物学的深刻理解，对于开发BH3模拟物（如BCL2选择性抑制剂Venetoclax）至关重要。我们审查了许多临床前研究，这些研究加深了我们对BCL2生物学的理解并促进了venetoclax的临床发展。

启示：对控制程序性细胞死亡的途径的基础研究为发现凋亡诱导剂，如委内瑞拉（venetoclax）铺平了道路，委内瑞拉是一种BCL2选择性抑制剂，最近已获得FDA和欧洲药品管理局的批准。迄今为止，旨在鉴定依赖BCL2的肿瘤类型的临床前研究已经很好地转化为临床，并且可能会继续为Venetoclax和其他BCL2家族抑制剂的临床发展提供信息。巨蟹座Discov; 7（12）；1376–93。©2017 AACR。