Abstract
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Benzamides / chemical synthesis
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Benzamides / pharmacology*
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Cell Line, Tumor
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Cell Proliferation
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Chemistry, Pharmaceutical / methods
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Histone Deacetylase Inhibitors
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Humans
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Inhibitory Concentration 50
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Mice
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Neoplasm Transplantation
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Benzamides
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Pyrimidines
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mocetinostat