The MCL-1 inhibitor S63845: an exciting new addition to the armoury of anti-cancer agents

Defects in apoptotic machinery have long been recognised as both a significant contributor to cancer development, and as an important mechanism by which tumour cells develop chemotherapeutic resistance. The resistance of multiple malignancies to apoptosis has been attributed to increases in a number of pro-survival BCL-2 family members (e.g., BCL-2, BCL-XL, MCL-1, BCL-W, BFL-1 and BCL-B), which prevent BAX/BAK-mediated mitochondrial outer membrane permeabilisation. Inhibitors targeting these BCL-2 family members have garnered significant interest with the most promising lead being the BH3 mimetic venetoclax (also known as ABT-199, and marketed as Venclexta™ and Venclyxto™), a selective inhibitor of the BCL-2 protein recently approved for 17p deletion chronic lymphocytic leukemia (CLL). In a phase I trial in relapsed or refractory CLL, venetoclax induced a 79% response rate (1) which has subsequently prompted further trials in other haematological malignancies. Despite this success in CLL, venetoclax used as a monotherapy in other haematological malignancies have shown poor response rates (2), mainly due to the reliance of other BCL-2 family members such as MCL-1 for cell survival in these cancers. Indeed, studies using genetic knockout models and RNA interference have demonstrated MCL-1 to be crucial for disease development and progression in acute myeloid leukaemia (AML) (3), MYC-driven lymphomas (4), and multiple myeloma (5), and a mechanism of venetoclax resistance in these cancers (6). Indirect approaches to target MCL-1 through transcriptional repression (7,8) or post-translational degradation (9) have recently been developed. However, direct targeting strategies with obatoclax, an inhibitor of MCL-1 and also BCL-2 and BCL-XL, induced neuronal toxicity (10,11). More recently, a reported MCL-1-selective inhibitor termed A-1210477 (12) displayed in vitro activity against multiple myeloma cells (13); however, these anti-cancer effects appear likely to result from combination of both targeting MCL-1 and off-target effects (14).