Abstract
In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC50 values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.
Keywords:
Antitumor activity; Design; HDAC; Synthesis; c-Met.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Assays
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Histone Deacetylase 1 / antagonists & inhibitors*
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / metabolism
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Phenylurea Compounds / chemical synthesis
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Phenylurea Compounds / metabolism
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Phenylurea Compounds / pharmacology
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Quinolines / chemical synthesis
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Quinolines / metabolism
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Quinolines / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Quinolines
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Proto-Oncogene Proteins c-met
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HDAC1 protein, human
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Histone Deacetylase 1