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 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.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chia-Hsien
CH
Wu
Mohane Selvaraj
MS
Coumar
Chang-Ying
CY
Chu
Wen-Hsing
WH
Lin
Yi-Rong
YR
Chen
Chiung-Tong
CT
Chen
Hui-Yi
HY
Shiao
Shaik
S
Rafi
Sing-Yi
SY
Wang
Hui
H
Hsu
Chun-Hwa
CH
Chen
Chun-Yu
CY
Chang
Teng-Yuan
TY
Chang
Tzu-Wen
TW
Lien
Ming-Yu
MY
Fang
Kai-Chia
KC
Yeh
Ching-Ping
CP
Chen
Teng-Kuang
TK
Yeh
Su-Huei
SH
Hsieh
John T-A
JT
Hsu
Chun-Chen
CC
Liao
Yu-Sheng
YS
Chao
Hsing-Pang
HP
Hsieh
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077156:Gefitinib; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C553260:1-(4-((2-hydroxy-1-phenylethyl)amino)-5,6,7,8-tetrahydropyrido(4',3'-4,5)thieno(2,3-d)pyrimidin-7-yl)-2-propen-1-one; C553261:4-(dimethylamino)-1-(4-(2-hydroxy-1-phenylethyl)amino-5,6,7,8-tetrahydropyrido(4',3'-4,5)thieno(2,3-d)pyrimidin-7-yl)-2-buten-1-one; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011743:Pyrimidines; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib