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

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.
Competing Interests: PAC: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. M-JO-R: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. RT: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. OA-P: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. GB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. WC: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SC: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SEB: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. CE: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SG: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. ADHB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. PH: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SMH: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. WK: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. AM: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. FRa: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. TR: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. FRo: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. KS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. RS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. MV: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SW: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. JB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. AB: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SAE: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SH: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. KU: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. PW: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. DW: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. The other authors declare that no competing interests exist.