MSC2530818 binds to CDK8 and CDK19 with similar affinity (IC50 of 4 nM). It effectively inhibits the phosphorylation of STAT1SER727 (a biomarker of CDK8 activity) in SW620 human colorectal cancer cells (pSTAT1SER727 IC50=8±2 nM). MSC2530818 shows effective inhibition of WNT-dependent transcription in human cancer cell lines with constitutively active WNT signaling. For instance, MSC2530818 inhibits luciferase readings from reporter genes in several cell lines with mutations activating the WNT pathway; LS174T (β-catenin mutant, IC50=32±7 nM), COLO205 (APC mutant, IC50=9±1 nM) and shows inhibition of WNT3a ligand-dependent reporter gene readings in PA-1 cells (IC50=52±30 nM). MSC2530818 exhibits minimal activity in the CEREP panel and minimal hERG inhibition. Additionally, MSC2530818 is a soluble CDK8 inhibitor with high permeability and low efflux in Caco-2 cells, and does not inhibit any cytochrome P450 subtypes[1].
MSC2530818 动物研究
Animal study
Treatment with MSC2530818 in tumor-bearing mice resulted in a reduction of tumor growth, with T/C ratios (based on final tumor weight) of 49% and 57%. MSC2530818 is generally well-tolerated, with once-daily dosing having no impact on mouse weight, and any weight loss being controllable. The estimated human clearance at steady state is low (0.14 L/h/kg) and the distribution volume is small (0.48 L/kg), leading to a predicted short terminal half-life of 2.4 hours. Physiologically-based pharmacokinetic simulations suggest that the oral bioavailability in humans at a daily dose of 500 mg could be higher than 75%[1].
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