TY - JOUR TI - Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases AU - Clarke, Paul A AU - Ortiz-Ruiz, Maria-Jesus AU - TePoele, Robert AU - Adeniji-Popoola, Olajumoke AU - Box, Gary AU - Court, Will AU - Czasch, Stephanie AU - El Bawab, Samer AU - Esdar, Christina AU - Ewan, Ken AU - Gowan, Sharon AU - De Haven Brandon, Alexis AU - Hewitt, Phillip AU - Hobbs, Stephen M AU - Kaufmann, Wolfgang AU - Mallinger, Aurélie AU - Raynaud, Florence AU - Roe, Toby AU - Rohdich, Felix AU - Schiemann, Kai AU - Simon, Stephanie AU - Schneider, Richard AU - Valenti, Melanie AU - Weigt, Stefan AU - Blagg, Julian AU - Blaukat, Andree AU - Dale, Trevor C AU - Eccles, Suzanne A AU - Hecht, Stefan AU - Urbahns, Klaus AU - Workman, Paul AU - Wienke, Dirk A2 - Cravatt, Benjamin F VL - 5 PY - 2016 DA - 2016/12/09 SP - e20722 C1 - eLife 2016;5:e20722 DO - 10.7554/eLife.20722 UR - https://doi.org/10.7554/eLife.20722 AB - 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 impact on 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 modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe 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 clinical development of CDK8/19 inhibitors. KW - CDK8 KW - inhibitor KW - Mediator complex KW - Wnt KW - super-enhancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -