A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

被引：43

作者：

Aguilar, Angelo ^{[1
,2
,3
,4
]}

Zhou, Haibin ^{[1
,2
,3
,4
]}

Chen, Jianfang ^{[1
,2
,3
,4
]}

Liu, Liu ^{[1
,2
,3
,4
]}

Bai, Longchuan ^{[1
,2
,3
,4
]}

McEachern, Donna ^{[1
,2
,3
,4
]}

Yang, Chao-Yie ^{[1
,2
,3
,4
]}

Meagher, Jennifer ^{[5
]}

Stuckey, Jeanne ^{[5
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

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

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

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

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 07期

基金：

美国国家卫生研究院;

关键词：

N BOND FORMATION; RECEPTOR ANTAGONISTS; MOLECULE INHIBITOR; ANTICANCER THERAPY; DESIGN; BCL-2; PROTEINS; RIMONABANT; REGRESSION; DISCOVERY;

D O I：

10.1021/jm4001105

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K-i values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.

引用

收藏

页码：3048 / 3067

页数：20

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