Cyclin-dependent kinase 8 and 19 (CDK8/19)

Cyclin-dependent kinase 8 (CDK8) and its paralog Cyclin-dependent kinase 19 (CDK19) are key enzymatic components of the Mediator complex, a multi-protein assembly that bridges DNA-bound transcription factors to the RNA polymerase II machinery (UniProt P49336, Q9BWU1). In Estrogen Receptor-positive (ER+) breast cancer, CDK8 and CDK19 act as critical co-regulators of ER-mediated transcriptional signaling, often facilitating the expression of genes involved in cell cycle progression and survival (McDermott et al., 2017, DOI: 10.18632/oncotarget.19250). These kinases can phosphorylate the Estrogen Receptor alpha (ERα) at Serine 118, a modification that enhances its transcriptional activity and contributes to resistance against standard endocrine therapies like tamoxifen (Roninson et al., 2019, DOI: 10.1016/j.cellsig.2019.03.010). By inhibiting CDK8/19, drugs can disrupt this specific transcriptional program without affecting the basal transcription required for normal cell survival. This makes the CDK8/19-ER axis a high-value target for overcoming drug resistance in hormone-dependent cancers. Several small-molecule inhibitors, such as RVU120 and Senexin B, are being investigated for their ability to suppress tumor growth by blocking this Mediator-dependent signaling (Ryvu Therapeutics, 2024). Clinical development focuses on using these inhibitors to treat advanced ER+ breast cancers and certain leukemias where CDK8/19 activity is dysregulated.

Other names

CDK8CDK19Mediator complex subunit CDK8Mediator complex subunit CDK19Cell division cycle 2-like protein kinase 6CDC2L6K35

Selective inhibition of the kinase activity of CDK8 and CDK19 within the Mediator complex, which prevents the phosphorylation and transcriptional activation of the Estrogen Receptor and other oncogenic transcription factors.