Design and Synthesis of Tetrahydropyridothieno[2,3-d]pyrimidine Scaffold Based Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain Chirality and Michael Acceptor Group for Maximal Potency

被引：110

作者：

Wu, Chia-Hsien ^{[1
]}

Coumar, Mohane Selvaraj ^{[1
]}

Chu, Chang-Ying ^{[1
]}

Lin, Wen-Hsing ^{[1
]}

Chen, Yi-Rong ^{[2
]}

Chen, Chiung-Tong ^{[1
]}

Shiao, Hui-Yi ^{[1
]}

Rafi, Shaik ^{[1
]}

Wang, Sing-Yi ^{[1
]}

Hsu, Hui ^{[1
]}

Chen, Chun-Hwa ^{[1
]}

Chang, Chun-Yu ^{[1
]}

Chang, Teng-Yuan ^{[1
]}

Lien, Tzu-Wen ^{[1
]}

Fang, Ming-Yu ^{[1
]}

Yeh, Kai-Chia ^{[1
]}

Chen, Ching-Ping ^{[1
]}

Yeh, Teng-Kuang ^{[1
]}

Hsieh, Su-Huei ^{[1
]}

Hsu, John T. -A. ^{[1
,4
]}

Liao, Chun-Chen ^{[3
,5
]}

Chao, Yu-Sheng ^{[1
]}

Hsieh, Hsing-Pang ^{[1
]}

机构：

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

[2] Natl Hlth Res Inst, Div Mol & Genom Med, Zhunan 350, Miaoli County, Taiwan

[3] Natl Tsing Hun Univ, Dept Chem, Hsinchu 300, Taiwan

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

[5] Chung Yuan Christian Univ, Dept Chem, Chungli 320, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 20期

关键词：

CELL LUNG-CANCER; TYROSINE KINASE; IRREVERSIBLE INHIBITOR; RESISTANCE; GEFITINIB; ANTITUMOR; MUTATION; HKI-272; HER-2;

D O I：

10.1021/jm100607r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

引用

页码：7316 / 7326

页数：11

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