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

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...

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Bibliographic Details
Published inChinese chemical letters Vol. 28; no. 6; pp. 1220 - 1227
Main Authors Ding, Chao, Li, Dan, Wang, Yan-Wei, Han, Sai-Sai, Gao, Chun-Mei, Tan, Chun-Yan, Jiang, Yu-Yang
Format Journal Article
LanguageEnglish
Published Elsevier B.V 01.06.2017
Subjects
Anticancer
HDAC
Kinase
Multitarget
Selectivity
Selectivity
Multitarget
Anticancer
Kinase
HDAC
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Summary: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.
Bibliography:11-2710/O6
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.
Anticancer Kinase HDAC Multitarget Selectivity
ISSN:1001-8417
1878-5964
DOI:10.1016/j.cclet.2017.01.003