AS2863619 enables conversion of antigen-specific effector/memory T cells into Foxp3+ regulatory T (Treg) cells for the treatment of various immunological diseases. AS2863619 is a potent, orally active cyclin-dependent kinase 8 (CDK8) and CDK19 inhibitor with IC50s of 0.61 nM and 4.28 nM, respectively. STAT5 activation enhanced by AS2863619 inhibition of CDK8/19, which consequently activates the Foxp3 gene[1].

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[1]. Western Blot Analysis[1] Cell Line: Mouse CD4+ T cells

AS2863619 (30 mg/kg; oral administration; daily; for 2 weeks; mice) treatment after sensitization with 2,4-dinitrofluorobenzene (DNFB) dampens the degree of the secondary response, with milder infiltration of inflammatory cells into the skin and decreases ratios of interferon-γ+ (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[1]. Animal Model: Mice with DNFB-induced contact skin hypersensitivity[1]

[1]. Akamatsu M, et al. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci Immunol. 2019 Oct 25;4(40). pii: eaaw2707.