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Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

Clarke, Paul Andrew, Ortiz-Ruiz, Maria-Jesus, TePoele, Robert, Adeniji-Popoola, Olajumoke, Box, Gary, Court, Will, Czasch, Stefanie, El Bawab, Samer, Esdar, Christina, Ewan, Kenneth Burnside Ramsay, Gowan, Sharon, De Haven Brandon, Alexis, Hewitt, Phllip, Hobbs, Stephen M, Kaufmann, Wolfgang, Mallinger, Aurélie, Raynaud, Florence, Roe, Toby, Rohdich, Felix, Schiemann, Kai, Simon, Stephanie, Schneider, Richard, Valenti, Melanie, Weigt, Stefan, Blagg, Julian, Blaukat, Andree, Dale, Trevor Clive, Eccles, Suzanne A., Hecht, Stefan, Urbahns, Klaus, Workman, Paul and Wienke, Dirk 2016. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. eLife 5 , e20722. 10.7554/eLife.20722

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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
Date Type: Published Online
Status: Published
Schools: Biosciences
Additional Information: This article is distributed under the terms of the Creative Commons Attribution License
Publisher: eLife Science Publications
ISSN: 2050-084X
Date of First Compliant Deposit: 20 September 2017
Date of Acceptance: 29 November 2016
Last Modified: 15 Jul 2019 11:44
URI: http://orca.cf.ac.uk/id/eprint/96966

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