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|Public on Dec 01, 2016
|Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
|Expression profiling by array
|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 limit 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 only modest efficacy against human tumor cell line or patient-derived xenografts. Expression profiling detected altered gene expression consistent with CDK8/19 inhibition, including profiles associated with superenhancer–regulated gene expression. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. Finally, in two species, neither test compound 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 further clinical development of CDK8/19 inhibitors.
|SW620 colon cancer cells were grown as xenografts in female NCr athymic mice and once established, treated twice daily with 70 mg/kg of Compound 1 or vehicle. Two and six hours after the final dose tumours were snap frozen. Tumour sample RNA was hybridised against human reference. Compound 1 is from a series of close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. It was shown to be a potent and selective inhibitor of the Mediator complex-associated protein kinases CDK8 and CDK19. It is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.
|Clarke PA, Ortiz-Ruiz M, te Poele RH, Adeniji-Popoola O, Box G, Court W, El Bawab S, Esdar C, Ewan K, Gowan S, de Haven Brandon A, Hewitt P, Hobbs SM, Kaufmann W, Mallinger A, Raynaud F, Toby R, Rohdich F, Schiemann K, Simon S, Schneider R, Valenti M, Blagg J, Blaukat A, Dale T, Eccles SA, Hecht S, Urbahns K, Workman P, Wienke D
|Apr 20, 2016
|Last update date
|Jan 09, 2018
|Robert te Poele
|The Institute of Cancer Research
|Cancer Reserach UK Unit for Cancer Therapeutics
|Signal Transduction and Molecular Pharmacology Team
|15 Cotswold Road
|Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)
|This SubSeries is part of SuperSeries:
|Assessing the mechanism and therapeutic potential of modulators of the human mediator complex-associated protein kinases
|TAR (of TXT)