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Title: Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases      
keywords:
Transcriptome or Gene expression
ID:
PRJNA319020
description:
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. Overall design: Colo205 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, 20 mg/kg of Compound 3 or vehicle. Two and six hours after the final dose tumours were snap frozen. Tumour sample RNA was hybridised against human reference. Compound 1 and 3 are 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. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors 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.
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA319020
authentication:
none
authorization:
none
ID:
pmid:27935476
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject