Clarke, Paul A., Ortiz-Ruiz, Maria-Jesus, TePoele, Robert, Adeniji-Popoola, Olajumoke, Box, Gary, Court, Will, Czasch, Stefanie, El Bawab, Samer, Esdar, Christina, Ewan, Ken ![]() ![]() ![]() |
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Abstract
Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with ontarget effects posing significant challenges to the clinical development of CDK8/19 inhibitors.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Biosciences European Cancer Stem Cell Research Institute (ECSCRI) |
Additional Information: | This article is distributed under the terms of the Creative Commons Attribution License. |
Publisher: | eLife Sciences Publications |
ISSN: | 2050-084X |
Date of First Compliant Deposit: | 20 September 2017 |
Date of Acceptance: | 29 November 2016 |
Last Modified: | 29 Jun 2023 09:42 |
URI: | https://orca.cardiff.ac.uk/id/eprint/96966 |
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