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.
Wu
Chia-Hsien
CH
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Coumar
Mohane Selvaraj
MS
Chu
Chang-Ying
CY
Lin
Wen-Hsing
WH
Chen
Yi-Rong
YR
Chen
Chiung-Tong
CT
Shiao
Hui-Yi
HY
Rafi
Shaik
S
Wang
Sing-Yi
SY
Hsu
Hui
H
Chen
Chun-Hwa
CH
Chang
Chun-Yu
CY
Chang
Teng-Yuan
TY
Lien
Tzu-Wen
TW
Fang
Ming-Yu
MY
Yeh
Kai-Chia
KC
Chen
Ching-Ping
CP
Yeh
Teng-Kuang
TK
Hsieh
Su-Huei
SH
Hsu
John T-A
JT
Liao
Chun-Chen
CC
Chao
Yu-Sheng
YS
Hsieh
Hsing-Pang
HP
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