Abstract
Novel substituted indolocarbazoles were synthesized, and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles 4 were found to be potent and selective D1/CDK4 inhibitors. 4d and 4h exhibited potent and ATP-competitive D1/CDK4 activities with IC50 values of 76 and 42 nM, respectively. Both compounds had high selectivity against the other kinases. These D1/CDK4 inhibitors inhibited tumor cell growth, arrested tumor cells at the G1 phase, and inhibited pRb phosphorylation.
MeSH terms
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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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Carbazoles / chemical synthesis*
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Carbazoles / chemistry
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Carbazoles / pharmacology
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Cell Division / drug effects
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Cyclin D1 / metabolism*
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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G1 Phase / drug effects
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Phosphorylation
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Proto-Oncogene Proteins*
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Retinoblastoma Protein / metabolism
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Carbazoles
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Enzyme Inhibitors
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Indoles
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Cyclin D1
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases