AS2863619 is an oral inhibitor of cyclin-dependent kinase 8 (CDK8) and CDK19. Inhibition of CDK8/19 can enhance the activation of STAT5, thereby activating the Foxp3 gene. It can convert antigen-specific effector/memory T cells into Foxp3+ regulatory T cells to study various immune diseases.

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

METHODS: Mouse CD4 T cells were treated with AS2863619 (1 μM; 22 hours), and the possible effects of AS2863619 on STAT5 phosphorylation during Foxp3 induction in Tconv cells were investigated.
RESULTS AS2863619 inhibited the PSP motif serine phosphorylation of STAT5b to about 40%, while increasing the tyrosine phosphorylation of the C-terminal domain to about 160%; the inhibitory effect of AS2863619 on STAT5b serine phosphorylation was dose-dependent with Foxp3 induction. [1]

METHODS: Mice were orally treated with AS2863619 (3, 10, or 30 mg/kg). Plasma samples were collected from mice at 1, 2, 4, 8, and 24 hours after administration, and drug levels were determined by high-performance liquid chromatography-tandem mass spectrometry.
RESULTS Compared with control mice, AS2863619 treatment after 2,4-dinitrofluorobenzene (DNFB) sensitization suppressed the extent of secondary responses, with less inflammatory cell infiltration into the skin and a lower proportion of interferon-γ (IFN-γ) cells in regional lymph nodes; depletion of Tregs abolished AS2863619-induced suppression before the induction of secondary responses. [1]