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Series GSE80471 Query DataSets for GSE80471
Status Public on Dec 01, 2016
Title Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
Organism Homo sapiens
Experiment type Expression profiling by array
Summary 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 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.
Contributor(s) 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
Citation(s) 27935476
Submission date Apr 20, 2016
Last update date Jan 09, 2018
Contact name Robert te Poele
Phone 00442087224319
Organization name The Institute of Cancer Research
Department Cancer Reserach UK Unit for Cancer Therapeutics
Lab Signal Transduction and Molecular Pharmacology Team
Street address 15 Cotswold Road
City Sutton
State/province Surrey
ZIP/Postal code SM2 5NG
Country United Kingdom
Platforms (1)
GPL17077 Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)
Samples (20)
GSM2127992 SW620_2_H_VEHICLE 1
GSM2127993 SW620_2_H_VEHICLE 2
GSM2127994 SW620_2_H_VEHICLE 3
This SubSeries is part of SuperSeries:
GSE80472 Assessing the mechanism and therapeutic potential of modulators of the human mediator complex-associated protein kinases
BioProject PRJNA319019

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE80471_RAW.tar 425.3 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

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