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

• DOI: 10.7554/elife.20722
• Publication Date: 2016-12-09T13:02:32Z
• Authors: Paul A Clarke; Maria-Jesus Ortiz...; Robert TePoele; Olajumoke Adeniji...; Gary Box; Will Court; Stephanie Czasch; Samer El Bawab; Christina Esdar; Ken Ewan; Sharon Gowan; Alexis De Haven B...; Phillip Hewitt; Stephen M Hobbs; Wolfgang Kaufmann; Aurélie Mallinger; Florence Raynaud; Toby Roe; Felix Rohdich; Kai Schiemann; Stephanie Simon; Richard Schneider; Melanie Valenti; Stefan Weigt; Julian Blagg; Andree Blaukat; Trevor C Dale; Suzanne A Eccles; Stefan Hecht; Klaus Urbahns; Paul Workman; Dirk Wienke
• Keywords: Mediator

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it unclear whether this will impact on the clinical utility inhibitors. We discovered two series potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence robust on-target activity, compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent inhibition, including profiles associated super-enhancers, immune inflammatory responses stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from transit amplifying phenotype. species, neither probe tolerated at therapeutically-relevant exposures. The complex nature toxicity observed structurally-differentiated effects posing significant challenges development