In vitro activity: MSC2530818 is novel, potent, selective and orally available small molecule inhibitor of cyclin dependent kinase CDK8 with the IC50 of 2.6 nM. It demonstrates excellent pharmacokinetics and pharmacodynamics including good kinase selectivity, high biochemical and cellular potency, microsomal stability, and reasonable oral bioavailability. The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. MSC2530818 was identified in a high-throughput screening campaign and further progressed by structure-based design. MSC2530818 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.

Kinase Assay: MSC2530818 is novel, potent, selective and orally available small molecule inhibitor of cyclin dependent kinase CDK8 with the IC50 of 2.6 nM.

Cell Assay: SC2530818 demonstrates potent inhibition of WNT-dependent transcription in human cancer cell lines that have constitutively activated WNT signaling. For example, MSC2530818 inhibits the reporter-based luciferase readout in several cell lines bearing activating WNT-pathway mutations; LS174T (β-catenin mutant, IC50=32±7 nM), COLO205 (APC mutant, IC50=9±1 nM) and demonstrates inhibition of WNT3a ligand-dependent reporter readout in PA-1 cells (IC50=52±30 nM). MSC2530818 demonstrates minimal activity in the CEREP panel, being active on the dopamine transporter (IC50=8.5 μM) as the only activity below 10 μM, and demonstrates minimal hERG inhibition. Furthermore, MSC2530818 is a soluble CDK8 inhibitor with high permeability and low efflux ratio in Caco-2 cells and does not inhibit any cytochrome P450 subtypes.