Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that plays crucial roles in the regulation of apoptosis in homeostatic cells.  As the over-expression of this protein has been associated with a myriad of lethal chemotherapeutically resistant cancers, Mcl-1 is a critical target for the design of small-molecule inhibitors.  Currently, no potent Mcl-1 selective inhibitors have reached clinical trials, emphasizing the urgent need for such clinically-effective and specific chemotherapeutics.  The oncogenic activity of Mcl-1 is mediated through protein�protein interactions with the pro-apoptotic members of the Bcl-2 family.  Specifically, a hydrophobic binding groove on Mcl-1 binds the BH3 a-helices of pro-apoptotic Bcl-2 proteins that include Bak and Bim, resulting in the regulation of intrinsic apoptosis.  In a structure-based drug design strategy, we have rationally engineered and synthesized small-molecules based on 1-hydroxy-2-carboxy-substituted arene motifs as specific inhibitors of Mcl-1.  Biological evaluation of our novel compounds is currently underway.

Design, synthesis, and biological evaluation of 1-hydroxy-2-carboxy-substituted arenes as selective inhibitors of the Mcl-1 oncoprotein

247th National Meeting (2014)

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