期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 8, 期 8, 页码 830-834出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00172
关键词
Dual c-Met/HDAC inhibitor; hybrid; designed multiple ligand (DML)
资金
- National Natural Science Foundation of China [81225022, 81321092, 81673472, 81402966]
- Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020105]
Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.
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