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

Elife. 2016 Dec 9;5:e20722. doi: 10.7554/eLife.20722.

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 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.

Keywords: CDK8; Mediator complex; Wnt; cancer biology; human; human biology; inhibitor; medicine; super-enhancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / toxicity
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / toxicity
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Hyperplasia / drug therapy
  • Mediator Complex / antagonists & inhibitors*
  • Mice
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / toxicity
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Mediator Complex
  • Protein Kinase Inhibitors
  • CDK19 protein, human
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases