Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib,BMS-690514,neratinib,and TAK-285

摘要

By combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib,BMS-690514,neratinib,and TAK-285 with 1,2,3-triazole as linker,eight novel 6-substituted-4-aminoquinazolin derivatives were synthesized and characterized by ~1H NMR,^(13)C NMR,and high resolution mass spectrometry.Their inhibitory activities against five enzymes(VEGFR2,HER2,EGFR,HDAC1,and HDAC6) and five cancer cell lines(A549,BT-474,A431,SK-BR-3,and NCI-H1975) were evaluated.The bioassay results show that the introduction of triazole linked vorinostat-like segment dramatically changed the selectivity profiles of newly synthetic compounds relative to vandetanib,BMS-690514,neratinib,and TAK-285.Among them,compound 6b exerted outstanding enzymatic and cellular activities through its simultaneous and synergistic inhibitions on multiple pathways,which might have the great potential to confer the better benefits than single-targeted inhibitors in cancer therapy.