Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach

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PROJECT SUMMARY Given the pivotal role of anti-apoptotic Bcl-2 family of proteins in cancer cell survival and resistance to chemotherapy, the development of novel anti-cancer therapeutics targeting the BH3 binding groove of anti- apoptotic Bcl-2 proteins have emerged as a promising, yet challenging therapeutic goal. The recent approval of Venetoclax (ABT199), a selective Bcl-2 antagonist whose design and development spanned well over fifteen years of iterative optimizations using extensive structure-based refinements, suggested that it is indeed possible, albeit extremely challenging, to attain inhibitors of protein-protein interactions (PPIs) that are clinically relevant. However, we and others found that overexpression of both Mcl-1 and, perhaps more relevant, Bfl-1 (two other members of the Bcl-2 family protein that are not targeted by Venetoclax), confer resistance to chemotherapy and to Bcl-2 antagonists. Recent efforts from our laboratory identified possible novel routes to design potent and selective inhibitors of PPIs targeting these oncogenes that encompass structure-based design of covalent inhibitors. Hence, we propose to further investigate these innovative structure-guided drug discovery strategies and to apply them to the design of potent dual Mcl-1/Bfl-1 antagonists. If successful, our studies could result in general methods to target PPIs and could also identify innovative lead compounds for the treatment of cancer.