Targeting Mediator Kinases CDK8 and CDK19: Unveiling the Therapeutic Potential of Preclinical Inhibitors

The article discusses the role of CDK8 and CDK19, which are part of the Mediator complex and linked to various cancers. It highlights the correlation between CDK8 expression and the activation of β-catenin in colon and gastric cancers, as well as its association with increased mortality in colorectal, breast, and ovarian cancers. The article also notes that CDK8 is found in a chromosomal region prone to copy number gain in colorectal cancers, and that reducing CDK8 protein levels can slow tumor growth in animal models.

The authors introduce CCT251545, a small molecule identified through a WNT pathway screen, and CCT251921, an inhibitor with optimized properties for preclinical development. They also mention MSC2530818, a structurally different candidate with a similar profile to CCT251921. These compounds were used to study the effects of inhibiting both CDK8 and CDK19, showing significant modulation of WNT signaling and other pathways related to stress and immune response.

The study reveals gene expression profiles influenced by the dual inhibition of CDK8 and CDK19, demonstrating the Mediator complex's role in gene transcription regulation. Both CCT251921 and MSC2530818 are shown to inhibit STAT1SER727 phosphorylation, a biomarker for CDK8 inhibition, and exhibit antiproliferative effects in animal models of colorectal cancer and acute myeloid leukemia.

The article presents preclinical data on the efficacy, toleration, and safety of CCT251921 and MSC2530818, suggesting their potential as novel anticancer therapeutics targeting CDK8. It also references a previous study on the identification of a chemical probe for CDK8 and CDK19 and includes a citation for a presentation at the American Association for Cancer Research annual meeting.