Abstract
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
MeSH terms
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Aminopyridines* / chemical synthesis
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Aminopyridines* / chemistry
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Aminopyridines* / pharmacology
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / metabolism
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Drug Discovery
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Drug Screening Assays, Antitumor
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Hematologic Neoplasms / drug therapy
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Hematologic Neoplasms / pathology
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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* / chemistry
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Histone Deacetylase Inhibitors* / pharmacology
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Histone Deacetylase Inhibitors* / therapeutic use
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasms / drug therapy
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Neoplasms / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Pyrimidines* / chemical synthesis
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Pyrimidines* / chemistry
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Pyrimidines* / pharmacology
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Pyrimidines* / therapeutic use
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Histone Deacetylase Inhibitors
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Antineoplastic Agents
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Aminopyridines
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Pyrimidines
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Protein Kinase Inhibitors
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Cyclin-Dependent Kinase 9
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Histone Deacetylase 1
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CDK9 protein, human
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fms-Like Tyrosine Kinase 3
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HDAC1 protein, human