The anti-apoptotic proteins, Bcl-2 and Bcl-xL, are key regulators of apoptosis and attractive new cancer therapeutic targets. Using a structure-based strategy, we have designed and optimized a new class of potent, specific and efficacious Bcl-2/Bcl-xL inhibitors to target the interactions of Bcl-2/Bcl-xL with their pro-apoptotic binding partners. Our best lead compounds bind to Bcl-2 and Bcl-xL proteins with subnanomolar affinities and function as potent and specific Bcl-2/Bcl-xL antagonists in cell-free functional assays. They inhibit cancer cell growth with IC50 values of 1 nM and are 10-100 times more potent than ABT-737 and ABT-263. They induce robust apoptosis in tumor cells at concentrations as low as 10 nM.  The best inhibitors induce rapid and complete tumor regression in animal models of human cancer at dose-schedules that show minimal toxicity to animals. High-resolution crystal structures of our inhibitors in complex with Bcl-xL provide a structural basis for their high affinity binding to their targets. Taken together, our potent and specific Bcl-2/Bcl-xL inhibitors represent exciting lead compounds for advanced preclinical development.

Structure-based design of potent and specific non-peptide small-molecule inhibitors of Bcl-2 and Bcl-XL as new anticancer agents

244th National Meeting (2012)

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