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J Med Chem. 2012 May 24;55(10):4664-82. doi: 10.1021/jm300178u. Epub 2012 May 10.

Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold.

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Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, United States.

Erratum in

  • J Med Chem. 2012 Jun 28;55(12):5987.


Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM.

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