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Abstract
AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.
Highlights
Introduction cMesenchymal–epithelial transition factor (c-Met), which is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) binding to hepatocyte growth factor, plays important roles in cancer formation, progression, dissemination, and drug resistance
The starting material crizotinib 1 was treated with intermediates 13a–13f or 13g– 13l to give condensed ester products 3a–3l, respectively, which were treated with freshly prepared hydroxylamine methanol solution to give target compounds 2a–2l
Note: For a description of the assay conditions, please see Huang et al[17] and Zhang et al18. aIC50 values are reported as the mean of at least two independent determinations with eight concentrations each. bUsed as a positive control
Summary
Introduction cMesenchymal–epithelial transition factor (c-Met), which is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) binding to hepatocyte growth factor, plays important roles in cancer formation, progression, dissemination, and drug resistance. The most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). E144 Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold Zhang et al Fig. 1 Structures of crizotinib and representative approved histone deacetylase inhibitor.
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