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Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives.

ABSTRACT: 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.

SUBMITTER: Lu D 

PROVIDER: S-EPMC5554914 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives.

Lu Dong D   Yan Juan J   Wang Lang L   Liu Hongchun H   Zeng Limin L   Zhang Minmin M   Duan Wenwen W   Ji Yinchun Y   Cao Jingchen J   Geng Meiyu M   Shen Aijun A   Hu Youhong Y  

ACS medicinal chemistry letters 20170718 8

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, <b>2m</b>, inhibited c-Met kinase and HDAC1, with IC<sub>50</sub> values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both  ...[more]

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