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

作　　者：Chao Ding Dan Li Yan-Wei Wang Sai-Sai Han Chun-Mei Gao Chun-Yan Tan Yu-Yang Jiang 

机构地区：[1]Department of Chemistry, Tsinghua University, Beijing 100084, China [2]The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen518055, China [3]Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China

出　　处：《Chinese Chemical Letters》2017年第6期1220-1227,共8页中国化学快报（英文版）

基　　金：supported by funding from the National Natural Science Foundation of China(No.21272134);Shenzhen Municipal Government(No.CXB201104210014A and20150113A0410006)

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.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.

关 键 词：Anticancer Kinase HDAC Multitarget Selectivity 

分 类 号：TQ460.1[化学工程—制药化工]