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

  • J Med Chem. 2010 Oct 28;53(20):7316-26. doi: 10.1021/jm100607r.
Chia-Hsien Wu  1 ,  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 ,  Tzu-Wen Lien ,  Ming-Yu Fang ,  Kai-Chia Yeh ,  Ching-Ping Chen ,  Teng-Kuang Yeh ,  Su-Huei Hsieh ,  John T-A Hsu ,  Chun-Chen Liao ,  Yu-Sheng Chao ,  Hsing-Pang Hsieh
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
PMID: 20961149 DOI: 10.1021/jm100607r
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.

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