AS2863619 free base enables the conversion of antigen-specific effector/memory T cells into Foxp3+ regulatory T (Treg) cells. It is a potent, orally active CDK8 and CDK19 inhibitor (IC50s: 0.61 nM and 4.28 nM). STAT5 activation enhanced by AS2863619 free base inhibition of CDK8/19, which consequently activates the Foxp3 gene.

GSK-3β:63.06 nM, GSK-3α:76.67 nM, CDK8:0.61 nM, STAT5:, CDK19:4.28 nM

AS2863619 (1 μM; 22 hours; mouse CD4+ T cells) treatment suppresses serine phosphorylation of the PSP motif of STAT5b to ~40% while enhancing tyrosine phosphorylation in the C-terminal domain to ~160% of control-treated samples.

AS2863619 (30 mg/kg; p.o.; daily; for 2 weeks; mice) treatment after sensitization with DNFB dampens the degree of the secondary response, with milder infiltration of inflammatory cells into the skin and decreases ratios of IFN-γ+ cells in a skin contact hypersensitivity model, when compared with vehicle-treated control mice. Treg depletion before the elicitation of the secondary response abolishes AS2863619-induced suppression. KLRG1+ Foxp3+ T cells are specifically increased in DNFB sensitized AS2863619-treated mice.