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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Macromolecular Structure and Function C Study Section (MSFC)
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Forry, Suzanne L
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University of California Riverside
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