Cyclin-dependent kinase 8 (CDK8) and its “twin” CDK19 are enzymatic components of the ‘CDK module’ associated with the multi-protein Mediator complex, which is involved in transcription (RNA synthesis). Mediator kinase cooperates with several different transcription factors to activate transcription of previously silent genes: transcriptional reprogramming. In contrast to some other proteins of the same CDK family (such as CDK4/6), CDK8/19 are not required for cell division, and long-term CDK8/19 inhibition has no major effects under normal conditions. Mediator kinase-mediated transcriptional reprogramming, however, plays a critical role in cancer, allowing tumor cells to adapt to adversarial conditions, growing at remote sites in the body (metastasis) and surviving therapeutic treatment (drug resistance). Such reprogramming has also been implicated in the development of several diseases other than cancer, including inflammation, viral diseases, auto-immune and cardiovascular diseases and osteoporosis. Senex has developed and chemically optimized the first selective small-molecule inhibitors of CDK8/19 and discovered novel uses for Mediator kinase inhibitors in the treatment of different diseases. Senex’s lead Mediator kinase inhibitor is currently undergoing Good Manufacturing Practice (GMP) production and preclinical development in preparation to clinical trials in prostate and breast cancers and leukemias.
(left) CDK8/19 Mediator kinase, in complex with other proteins of the CDK module and the core Mediator complex, cooperates with different signal-responsive transcription factors (inner circle) to reprogram cellular gene expression. Mediator kinase-driven transcriptional reprogramming plays a key role in different diseases, potential targets for CDK8/19 inhibitor therapy.
(right) CDK8/19 selectivity: effects of one of Senex’s inhibitors (tested at 2 uM) on 442 kinases. Red circles: inhibited kinases.
Inhibition of leukemia growth in mice by Senex’s Mediator kinase inhibitor (bioluminescence imaging)