Abstract
A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity. Compound 6e induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with 6e showed significant antitumor efficacy. The insight into mechanisms of 6e indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound 6e could be a promising drug candidate for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Cell Cycle Checkpoints / drug effects
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
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Female
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Histone Deacetylase 1 / antagonists & inhibitors*
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / pharmacokinetics
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Phosphorylation / drug effects
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Structure-Activity Relationship
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Substrate Specificity
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Tumor Suppressor Protein p53
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CDK4 protein, human
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CDK9 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 9
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Histone Deacetylase 1