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 G
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- 作者：Chia-Hsien Wu ; Mohane Selvaraj Coumar ; Chang-Ying Chu ; Wen-Hsing Lin ; Yi-Rong Chen ; Chiung-Tong Chen ; Hui-Yi Shiao ; Shaik Rafi ; Sing-Yi Wang ; Hui Hsu ; Chun-Hwa Chen ; Chun-Yu Chang ; Teng-Yuan Chang ; Tz
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：October 28, 2010
- 年：2010
- 卷：53
- 期：20
- 页码：7316-7326
- 全文大小：991K
- 年卷期：v.53,no.20(October 28, 2010)
- ISSN：1520-4804
文摘
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.