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.
Our studies are aimed at the identification of innovative agents capable of antagonizing anti-apoptotic proteins Bfl-1 and Mcl-1, responsible for cancer cell resistance. We will optimize the novel, irreversible Bfl-1 and Mcl-1 agents that we have recently discovered, and subsequently we will use pharmacological studies to assess their potential anti-cancer activity against melanoma and leukemia.
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