Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.
View/ Open
Date
2016-12-09Author
Clarke, PA
Ortiz-Ruiz, M-J
TePoele, R
Adeniji-Popoola, O
Box, G
Court, W
Czasch, S
El Bawab, S
Esdar, C
Ewan, K
Gowan, S
De Haven Brandon, A
Hewitt, P
Hobbs, SM
Kaufmann, W
Mallinger, A
Raynaud, F
Roe, T
Rohdich, F
Schiemann, K
Simon, S
Schneider, R
Valenti, M
Weigt, S
Blagg, J
Blaukat, A
Dale, TC
Eccles, SA
Hecht, S
Urbahns, K
Workman, P
Wienke, D
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Neoplasms
Disease Models, Animal
Hyperplasia
Cyclin-Dependent Kinases
Anti-Inflammatory Agents
Antineoplastic Agents
Protein Kinase Inhibitors
Treatment Outcome
Cyclin-Dependent Kinase 8
Mediator Complex
Heterografts
Research team
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Language
eng
Date accepted
2016-11-29
License start date
2016-12-09
Citation
eLife, 2016, 5
Publisher
ELIFE SCIENCES PUBLICATIONS LTD