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

ABSTRACT: 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.

SUBMITTER: Zhou H 

PROVIDER: S-EPMC3397176 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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

Zhou Haibin H   Chen Jianfang J   Meagher Jennifer L JL   Yang Chao-Yie CY   Aguilar Angelo A   Liu Liu L   Bai Longchuan L   Cong Xin X   Cai Qian Q   Fang Xueliang X   Stuckey Jeanne A JA   Wang Shaomeng S  

Journal of medicinal chemistry 20120510 10

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 b  ...[more]