Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: Combined ligand and target-based approach

被引：126

作者：

Gundla, Rambabu ^{[1
]}

Kazemi, Roza ^{[1
]}

Sanam, Ramadevi ^{[2
]}

Muttineni, Ravikumar ^{[2
]}

Sarma, Jagarlapudi A. R. P. ^{[2
]}

Dayam, Raveendra ^{[1
]}

Neamati, Nouri ^{[1
]}

机构：

[1] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA

[2] GVK Biosci Pvt Ltd, Div Informat, Technocrats Ind Estate, Hyderabad, Andhra Pradesh, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 12期

关键词：

D O I：

10.1021/jm7013875

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 mu M. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.

引用

页码：3367 / 3377

页数：11

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