Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
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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 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.
ORGANISM(S): Homo sapiens
PROVIDER: GSE80470 | GEO | 2016/12/01
SECONDARY ACCESSION(S): PRJNA319020
REPOSITORIES: GEO
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