Abstract
The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals and have been shown to be hijacked to sustain hyperproliferation by various solid and liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report the discovery of compound 12, a novel small molecule CDK8/19 inhibitor. This molecule demonstrated not only decent enzymatic and cellular activities but also remarkable selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.
MeSH terms
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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* / pharmacokinetics
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 8* / antagonists & inhibitors
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Cyclin-Dependent Kinase 8* / metabolism
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Cyclin-Dependent Kinases* / antagonists & inhibitors
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Cyclin-Dependent Kinases* / metabolism
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Drug Discovery
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Humans
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Mice
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Neoplasms / drug therapy
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacokinetics
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Protein Kinase Inhibitors* / pharmacology
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Protein Kinase Inhibitors* / therapeutic use
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Rats
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Structure-Activity Relationship
Substances
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Cyclin-Dependent Kinase 8
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Protein Kinase Inhibitors
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Cyclin-Dependent Kinases
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Antineoplastic Agents
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CDK8 protein, human
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CDK19 protein, human