The Bcl-2 proteins are key regulators of apoptosis.  Overexpression of the pro-survival members, including Bcl-2 and Bcl-xL, is a common feature in many tumors and small-molecule inhibitors against these pro-survival Bcl-2 proteins may hold great promise as new anticancer agents. Starting from the crystal structure of a very weak lead compound with a new scaffold, we have designed highly potent and new small-molecule inhibitors of Bcl-2/Bcl-xL. The most promising compound binds to Bcl-2 and Bcl-xL with Ki values < 1 nM, potently inhibits cell growth and induces apoptosis against lung and leukemia cancer cells and is capable of inducing tumor regression in the H-146 lung cancer xenograft model. Herein we describe the detailed SAR studies of these new and potent Bcl-2/Bcl-xL inhibitors.

Structure-activity relationship studies of new and highly potent small molecule Bcl-2/Bcl-xL inibitors

243rd National Meeting (2012)

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