In vitro: MSC2530818 binds to CDK8 and CDK19 with similar affinity (4 nM) and shows potent inhibition of phospho-STAT1SER727 in SW620 human colorectal carcinoma cells (IC50=8 ± 2 nM). It also demonstrates potent inhibition of WNT-dependent transcription in human cancer cell lines that have constitutively activated WNT signaling. MSC2530818 is a soluble CDK8 inhibitor with high permeability and low efflux ratio in Caco-2 cells (ER = 1.5) and does not inhibit any cytochrome P450 subtypes (Cyp IC50s > 20 μM).
In vivo: MSC2530818 shows acceptable pharmacokinetics (PK) in all tested preclinical species (mouse, rat, dog). It demonstrates reduction of tumor growth rates of established human SW620 colorectal carcinoma xenografts.
|Animal models||NCr athymic mice|
|Formulation||kolliphor 20% w/v in water|
|Dosages||50 mg/kg bid or 100 mg/kg qd|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||68 mg/mL in DMSO|
Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.
Czodrowski P, et al. J Med Chem. 2016 Oct 27;59(20):9337-9349. PMID: 27490956.
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LY-3177833 is a potent and selective inhibitor of CDC7 with IC50 of 3.3 nM.
Voruciclib (P1446A-05) is a protein kinase inhibitor specific for the cyclin-dependent kinase 4 (CDK4) with IC50s of 90nM, 25nM, and 22nM for CDK4-CyclinD1, CDK1-Cyclin B, and CDK9-Cyclin T, respectively.
CVT-313 is a potent and selective inhibitor of CDK2 that prevents neointimal proliferation, which has an IC50 of 0.5 microM in vitro.
ON123300 is a potent inhibitor of CDK4, with an IC50 of 3.8 nM, with little inhibitory activity against CDKs 1,2,5 and 8.
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