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

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elife-20722-v3.pdf (5.05 MB)

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ICR Authors

Clarke, Paul
 Gowan, Sharon
 Raynaud, Florence
 Workman, Paul

Authors

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

Document Type

Journal Article

Date

2016-12-09

Date Accepted

2016-11-29

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.

Citation

eLife, 2016, 5

DOI

10.7554/elife.20722

URI

https://repository.icr.ac.uk/handle/internal/3022

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

ELIFE SCIENCES PUBLICATIONS LTD

ISSN

2050-084X

eISSN

2050-084X

Collections

Cancer Therapeutics

Research Team

Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology

Notes