Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification

被引：65

作者：

Coumar, Mohane Selvaraj ^{[1
]}

Chu, Chang-Ying ^{[1
]}

Lin, Cheng-Wei ^{[1
,2
]}

Shiao, Hui-Yi ^{[1
]}

Ho, Yun-Lung ^{[1
]}

Reddy, Randheer ^{[1
]}

Lin, Wen-Hsing ^{[1
]}

Chen, Chun-Hwa ^{[1
]}

Peng, Yi-Hui ^{[1
]}

Leou, Jiun-Shyang ^{[1
]}

Lien, Tzu-Wen ^{[1
]}

Huang, Chin-Ting ^{[1
]}

Fang, Ming-Yu ^{[1
]}

Wu, Szu-Huei ^{[1
]}

Wu, Jian-Sung ^{[1
]}

Chittimalla, Santhosh Kumar ^{[1
]}

Song, Jen-Shin ^{[1
]}

Hsu, John T. -A. ^{[1
,3
]}

Wu, Su-Ying ^{[1
]}

Liao, Chun-Chen ^{[2
,4
]}

Chao, Yu-Sheng ^{[1
]}

Hsieh, Hsing-Pang ^{[1
]}

机构：

[1] Natl Hlth Res Inst, Div Biotechnol & Pharmaceut Res, Zhunan 350, Miaoli County, Taiwan

[2] Natl Tsing Hua Univ, Dept Chem, Hsinchu 300, Taiwan

[3] Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu 300, Taiwan

[4] Chung Yuan Christian Univ, Dept Chem, Zhongli 320, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 13期

关键词：

LUNG-CANCER; DRUG DESIGN; POTENT; CHEMISTRY; DISCOVERY; INSIGHTS; BINDING; MODELS; SAR;

D O I：

10.1021/jm1000198

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit la was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit Is, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

引用

页码：4980 / 4988

页数：9

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