Abstract 4851: Selective small molecule inhibition of anti-apoptotic MCL-1

BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. Anti-apoptotic members such as BCL-2, BCL-XL, and MCL-1 have been implicated in the initiation, progression, and chemoresistance of human cancer. The anti-apoptotic BCL-2/BCL-XL groove that binds and sequesters pro-apoptotic BH3 death helices has been successfully targeted by small molecules and peptides. Such compounds induce tumor cell apoptosis and are being advanced in clinical trials as promising next-generation cancer therapeutics. Notably, selective antagonists such as ABT-737 are highly effective at inducing apoptosis in BCL-2/BCL-XL-dependent cancers, but are rendered inactive by overexpression of MCL-1, a formidable chemoresistance protein that lies outside the molecule's binding spectrum. By screening a library of Stabilized Alpha-Helix of BCL-2 domains (SAHBs), we previously discovered that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor (Stewart et al., Nat Chem Biol, 2010). Here, we deployed this natural peptidic inhibitor of MCL-1 in a competitive binding screen to identify an MCL-1 inhibitor molecule (MIM) that displays exquisite selectivity in in vitro binding and functional assays. NMR analysis documented that MIM engages the canonical BH3-binding pocket of MCL-1. Importantly, MIM selectively triggers caspase 3/7 activation and apoptosis in a cancer cell line that is dependent on induced overexpression of MCL-1, but showed no activity in the isogenic cell line that is driven instead by overexpressed BCL-XL. Conversely, ABT-737 manifested activity in the BCL-XL-overexpressing cancer cells but had no effect on the corresponding MCL-1-dependent cells. Thus, we report the application of MCL-1 SAHB to identify a selective small molecule inhibitor of MCL-1 that exhibits pro-apoptotic activity in the specific context of MCL-1 dependence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4851. doi:1538-7445.AM2012-4851