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Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.

ABSTRACT: Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.

SUBMITTER: Zhou H

PROVIDER: S-EPMC3417242 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.

Zhou Haibin H Aguilar Angelo A Chen Jianfang J Bai Longchuan L Liu Liu L Meagher Jennifer L JL Yang Chao-Yie CY McEachern Donna D Cong Xin X Stuckey Jeanne A JA Wang Shaomeng S

Journal of medicinal chemistry 20120702 13

Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl ...[more]

PMID: 22747598

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