Citation: Chao Ding, Dan Li, Yan-Wei Wang, Sai-Sai Han, Chun-Mei Gao, Chun-Yan Tan, Yu-Yang Jiang. Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib, BMS-690514, neratinib, and TAK-285[J]. Chinese Chemical Letters, ;2017, 28(6): 1220-1227. doi: 10.1016/j.cclet.2017.01.003 shu

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

Chao Ding ^a,b ,
Dan Li ^a,b ,
Yan-Wei Wang ^a,b ,
Sai-Sai Han ^a,b ,
Chun-Mei Gao ^b ,
Chun-Yan Tan ^b,, ,
Yu-Yang Jiang ^a,c,,

a.
Department of Chemistry, Tsinghua University, Beijing 100084, China
b.
The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
c.
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China

Corresponding author: Chun-Yan Tan, tancy@sz.tsinghua.edu.cn Yu-Yang Jiang, jiangyy@sz.tsinghua.edu.cn
Received Date: 13 October 2016
Revised Date: 23 November 2016
Accepted Date: 13 December 2016
Available Online: 7 June 2017

Figures(5)

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, ¹³C 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
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