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

Author:

Clarke Paul A1ORCID,Ortiz-Ruiz Maria-Jesus1,TePoele Robert1,Adeniji-Popoola Olajumoke1,Box Gary1,Court Will1,Czasch Stephanie2,El Bawab Samer2,Esdar Christina2,Ewan Ken3,Gowan Sharon1,De Haven Brandon Alexis1,Hewitt Phillip2,Hobbs Stephen M1,Kaufmann Wolfgang2,Mallinger Aurélie1,Raynaud Florence1,Roe Toby1,Rohdich Felix2,Schiemann Kai2,Simon Stephanie2,Schneider Richard2,Valenti Melanie1,Weigt Stefan2,Blagg Julian1ORCID,Blaukat Andree2,Dale Trevor C3,Eccles Suzanne A1,Hecht Stefan2,Urbahns Klaus2,Workman Paul1ORCID,Wienke Dirk2

Affiliation:

1. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom

2. Merck KGaA, Darmstadt, Germany

3. School of Bioscience, Cardiff University, Cardiff, United Kingdom

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 on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.

Funder

Breast Cancer Now

Cancer Research UK

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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