Title: | 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 |
Authors: | Wu, Chia-Hsien Coumar, Mohane Selvaraj Chu, Chang-Ying Lin, Wen-Hsing Chen, Yi-Rong Chen, Chiung-Tong Shiao, Hui-Yi Rafi, Shaik Wang, Sing-Yi Hsu, Hui Chen, Chun-Hwa Chang, Chun-Yu Chang, Teng-Yuan Lien, Tzu-Wen Fang, Ming-Yu Yeh, Kai-Chia Chen, Ching-Ping Yeh, Teng-Kuang Hsieh, Su-Huei Hsu, John T. -A. Liao, Chun-Chen Chao, Yu-Sheng Hsieh, Hsing-Pang 生物科技學系 Department of Biological Science and Technology |
Issue Date: | 28-Oct-2010 |
Abstract: | 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. |
URI: | http://dx.doi.org/10.1021/jm100607r http://hdl.handle.net/11536/32051 |
ISSN: | 0022-2623 |
DOI: | 10.1021/jm100607r |
Journal: | JOURNAL OF MEDICINAL CHEMISTRY |
Volume: | 53 |
Issue: | 20 |
Begin Page: | 7316 |
End Page: | 7326 |
Appears in Collections: | Articles |
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