A 2,6-disubstituted 4-anilinoquinazoline derivative facilitates cardiomyogenesis of embryonic stem cells.
Chemical approaches are widely used in directed differentiation of embryonic stem (ES) cells. In our search for novel lead compounds that could facilitate cardiomyogenesis of ES cells, we designed a two-step screening system based on P19 embryonic carcinoma and mouse ES cells. Application of this system to a quinazoline compound library including 2,3-disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines and 2,6-disubstituted 4-anilinoquinazoline led us to the discovery of compound 62, which exhibits a stable cardiomyogenic effect on both P19 and mouse ES cells at a concentration of 0.1 μM. An EGFR inhibition assay and molecular docking studies confirmed 62 as a potent EGFR inhibitor with a tyrosine kinase IC(50) value of 101 nM. However, major differences in cardiomyogenic activity were observed between iressa and 62, indicating that other molecular events are also involved in compound 62-induced cardiomyogenesis of ES cells.
Institute of Pharmacology, Toxicology, and Biochemical Pharmeceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou, 310058, China.
Guofang
G
Shen
Ying
Y
Hu
Jianwei
J
Wu
Ke
K
Jin
Danyan
D
Zhu
Yandong
Y
Zhang
Yongping
Y
Yu
Yijia
Y
Lou
D000185:Actinin / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000166:cytology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012518:Sarcomeres / Q000378:metabolism; D054852:Small Molecule Libraries
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D054852:Small Molecule Libraries; D000185:Actinin; D009320:Atrial Natriuretic Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases