P001 The novel DYRK1a inhibitor VRN024219 alleviates disease severity on the IBD mouse models by modulating T-cell differentiation

Abstract

Abstract Background DYRK1A belongs to dual-specificity tyrosine (Y) phosphorylation regulated kinase (DYRK) family which is known to be activated through autophosphorylation of tyrosine residues in the activation loop and phosphorylates their substrates on serine and threonine residues. Other members of this family include DYRK1B, DYRK2, DYRK3, and DYRK4. Studies have revealed that DYRK kinase family plays an important role in regulating cell proliferation and apoptosis. DYRK1A has been reported to be strongly expressed in the brain and known to regulate various functions. However, the role and underlying mechanisms of DYRK1a in inflammation in general, specifically in IBD, remain poorly understood. Accordingly, we present the underlying mechanisms of DYRK1a on the course of IBD by using the novel DYRK1a inhibitor VRN024219. Methods First, we tested the effects of our compound VRN024219 on T-cell differentiation using naïve CD4 T cells extracted from the mouse spleen. Then we assessed the efficacy and mechanism of VRN024219 on the dextran sodium sulphate (DSS) and T-cell transfer-induced experimental colitis that mimics human ulcerative colitis (UC), comparing to that of Tofacitinib. Finally, we evaluated the effect of VRN024219 on pro-inflammatory cytokines such as interleukin (IL) −17A, IL-6, and tumour necrosis factor (TNF) α expressed by peripheral blood mononuclear cells (PBMCs) from 20 UC patient samples (Severance Hospital, Seoul, Korea). Results When VRN024219 was treated to splenocyte, the compound significantly downregulated Th17 and enhanced T reg cell differentiation. Protein levels of IL-17a, IL-6, and TNF α were increased in the DSS-induced colitis mice, whereas administration of DYRK1a inhibitor VRN024219 substantially improved clinical score than that of Tofacitinib-treated group. Additionally from T-cell transfer-induced colitis model, VRN024219 treated group demonstrated a larger population of ROR γ T-cell than that of tofacitinib Finally, the protein levels of proinflammatory cytokines were significantly down-regulated in VRN024219 treated 20 patient samples. Conclusion Our data provide clear evidence that the novel DYRK1a inhibitor plays a protective role in DSS- and T-cell transfer-induced colitis which was closely related to a Th17/Treg modulation. Thus, VRN024219 might a promising candidate for a new drug for IBD.