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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-10, Vol.53 (20), p.7316-7326
Main 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
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Drug Design
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Heterocyclic Compounds, 3-Ring - chemical synthesis
Heterocyclic Compounds, 3-Ring - chemistry
Heterocyclic Compounds, 3-Ring - pharmacology
Humans
Male
Mice
Mice, Nude
Mutation
Neoplasm Transplantation
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Quinazolines - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Stereoisomerism
Structure-Activity Relationship
Transplantation, Heterologous
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100607r