Authors
Le Bihan, Y. V., Foll-Josselin, B., Robert, T., Duez, J., Angevin, L., Simboeck, E., Prieto, S., Hodimont, E., Ferrer, J.-L., Krasinska, L., Ruchaud, S., Fisher, D.
Abstract
Protein kinase inhibitors are a key class of targeted cancer therapies, but finding compounds that show on-target efficacy with minimal toxicity remains challenging. CDK8 and CDK19 are paralogous kinases that regulate Mediator complex to promote transcriptional responses to extracellular signals and have also been reported to facilitate genome replication. Preclinical studies show that CDK8/19 inhibitors may have therapeutic benefit in several cancers, but whether effective inhibition of Mediator kinases is cytotoxic is debated. Here, we present a multi-modal approach for discovery of specific kinase inhibitors, and find that most CDK8/19 inhibitors show off-target toxicity and/or insufficient on-target engagement in cells. We describe several novel high affinity CDK8/19 inhibitors, report that loss of CDK8/19 activity is not cytotoxic but reduces cell proliferation without affecting DNA replication, and provide evidence that most inhibitors can bind in type I or type II modes. Our approach is applicable to any kinase inhibitor development program.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 08 Nov 2025.
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