MSC2530818 is an effective, selective and orally available CDK8 inhibitor (IC50: 2.6 nM).

CDK8:2.6 nM (cell free)

MSC2530818 binds to CDK8 and CDK19 with a similar affinity (4 nM) and shows potent inhibition of phospho-STAT1SER727, a biomarker of CDK8 activity, in SW620 human colorectal carcinoma cells (pSTAT1SER727 IC50=8±2 nM). It also inhibits WNT-dependent transcription in human cancer cell lines with activated WNT signaling, including LS174T (β-catenin mutant, IC50=32±7 nM), COLO205 (APC mutant, IC50=9±1 nM), and WNT3a ligand-dependent reporter readout in PA-1 cells (IC50=52±30 nM). Moreover, MSC2530818 exhibits a low efflux ratio in Caco-2 cells and does not inhibit any cytochrome P450 subtypes.

Treatment with MSC2530818 in mice carrying tumors resulted in a notable reduction of tumor growth, presenting T/C ratios of 49% and 57%. This compound was well accepted, showing no impact on the body weight of mice under a daily (qd) administration regimen, aside from controllable body weight loss. Additionally, its pharmacokinetic profile in humans indicates a low clearance (0.14 L/h/kg) and a small volume of distribution at steady-state (0.48 L/kg), leading to a brief estimated terminal half-life of 2.4 hours. Moreover, physiologically based pharmacokinetic simulations predict that MSC2530818 could achieve an oral bioavailability of at least 75% when administered up to a daily dose of 500 mg.

MSC2530818 is assessed in an established SW620 human colorectal cancer xenograft model in female NCr athymic mice. Tumor-bearing mice are treated orally with MSC2530818 (50 mg/kg bid or 100 mg/kg qd) for 16 days. Tumor weights are measured and body weights are monitored [1].