Found in translation: How preclinical research is guiding the clinical development of the BCL2-selective inhibitor venetoclax

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a highpriority goal for cancer therapy. After decades of effort, drugdiscovery scientists have succeeded in generating smallmolecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structurebased drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2selective 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 apoptosisinducing agents such as venetoclax, a BCL2selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2dependent 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.