CDK8-IN-15 (Compound 46) is a potent inhibitor of CDK8, exhibiting an IC50 value of 57 nM. This compound enhances the thermal stability of CDK8 and inhibits NF-κB, while selectively targeting the CDK family and tyrosine kinases. Additionally, it actively counteracts TNF-α-induced psoriasis in vitro and boosts the expression of Foxp3 and IL-10, potentially diminishing inflammatory responses and showing promise for research into psoriasis treatments.

CDK8:57 nM

CDK8-IN-15 exhibits the highest activity against CDK8 with an IC50 value of 57.3 nM and shows a positive effect in the HaCat cell model on TNF-α-induced psoriasis, with an IC50 value of 4.6 μM. At a concentration of 5 μM for 4 hours, CDK8-IN-15 inhibits CDK8 enzyme activity and enhances the thermal stability of both endogenous and exogenous CDK8 in HEK293T-CDK8 cells. Additionally, treatment with CDK8-IN-15 at concentrations of 0, 1, 2, and 4 μM for 75 hours significantly reduces the levels of CXCL1, CXCL2, and IL-8 in HEK293 cells.

CDK8-IN-15, administered to rats at dosages of 2 mg/kg intravenously and 10 mg/kg orally, exhibited high Caco-2 permeability and did not significantly inhibit five cytochrome P450 isoenzymes. In ICR mice, a single 1000 mg/kg oral dose of CDK8-IN-15 did not result in noticeable tissue damage. Moreover, in a psoriasis model induced by imiquimod in mice, oral doses of 5, 10, and 20 mg/kg of CDK8-IN-15 potentially alleviated symptoms by targeting CDK8, which enhances the production of IL-10 and expression of Foxp3. This compound demonstrates promising pharmacological properties and tissue compatibility, furthering its potential therapeutic applications.