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Keywords:

  • cardiomyogenesis;
  • drug discovery;
  • embryonic stem cells;
  • quinazolines;
  • solid-phase synthesis

Abstract

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 IC50 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.