Structure-Based Design of Potent Bcl-2/Bcl-xL Inhibitors with Strong in Vivo Antitumor Activity

被引：51

作者：

Zhou, Haibin ^{[2
,3
,4
,5
]}

Aguilar, Angelo ^{[2
,3
,4
,5
]}

Chen, Jianfang ^{[2
,3
,4
,5
]}

Bai, Longchuan ^{[2
,3
,4
,5
]}

Liu, Liu ^{[2
,3
,4
,5
]}

Meagher, Jennifer L. ^{[1
]}

Yang, Chao-Yie ^{[2
,3
,4
,5
]}

McEachern, Donna ^{[2
,3
,4
,5
]}

Cong, Xin ^{[2
,3
,4
,5
]}

Stuckey, Jeanne A. ^{[1
]}

Wang, Shaomeng ^{[2
,3
,4
,5
]}

机构：

[1] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 13期

基金：

美国国家卫生研究院;

关键词：

N BOND FORMATION; FAMILY PROTEINS; BCL-2; ANTAGONISTS; DISCOVERY; BCL-X(L); LIFE;

D O I：

10.1021/jm300608w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 angstrom 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 IC50 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.

引用

页码：6149 / 6161

页数：13

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