The development of selective inhibitors for the individual anti-apoptotic BCL-2 family proteins implicated in oncogenesis and chemoresistance remains a formidable but pressing challenge. Precisely tailored compounds would serve as ideal molecular probes and targeted therapies to respectively study and treat human cancers driven by discrete apoptotic blockades. The remarkable potential of this strategy is exemplified by ABT-199, a potent and selective small molecule BCL-2 inhibitor that is proving effective at reactivating apoptosis in BCL-2-dependent cancers. The BCL-2 protein homologue, BFL-1/A1, has emerged as a resistance factor in a series of human cancers, including melanoma, leukemia, and lymphoma, but remains undrugged. To identify binding and specificity determinants for targeting BFL-1/A1, we screened a library of hydrocarbon-stapled BH3 domain helices and identified a subclass of compounds that engage BFL-1/A1 with exquisite selectivity in vitro and in situ. The mechanistic basis for this specificity revealed a unique topographic feature of the BFL-1/A1 binding groove. Leveraging this natural BFL-1/A1 selectivity factor, we designed next-generation stapled peptide inhibitors that block BFL-1/A1's capacity to both bind BH3 domains and suppress BAX-mediated membrane poration. Our studies inform a new pharmacologic strategy for potent and selective inhibition of anti-apoptotic BFL-1/A1 in human cancer.

Citation Format: Annissa J. Huhn, Rachel M. Guerra, Gregory H. Bird, Loren D. Walensky. A novel selectivity determinant informs the development of next-generation stapled peptide inhibitors of anti-apoptotic BFL-1/A1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3845.