GLPG0634 analogue

GLPG0634 is a potent and selective inhibitor of JAK1 with IC50 values of 10, 28, 810 and 116 nM for JAK1, JAK2, JAK3 and TYK2, respectively [1].

Janus kinase 1 (JAK1) is a member of the JAK family and is a non-receptor tyrosine kinase. JAKs play an important role in the immune system. JAK1 is a potential target for the treatment of immune-inflammatory diseases [1].

GLPG0634 is a potent and selective JAK1 inhibitor. GLPG0634 inhibited JAK1, JAK2, JAK3 and TYK2 with IC50 values of 10, 28, 810 and 116 nM, respectively. In CD4+ T cells, GLPG0634 significantly reduced IL-6-induced STAT1 phosphorylation with IC50 value of 629 nM, which suggested the inhibition of JAK1. In CD33+ T cells, GLPG0634 reduced GM-CSF-induced STAT5 phosphorylation with IC50 value of 17.5 µM, suggesting the inhibition of JAK2. GLPG0634 inhibited the differentiation of Th1 and Th2 cells mediated by IL-4 and IL-12, respectively. Also, GLPG0634 inhibited Th17 differentiation induced by TGF-β, IL-23, IL-6 and IL-1β [1].

In rats, GLPG0634 significantly reduced the mRNA levels of Mx2, which were modulated by IFN-α-JAK1/TYK2 signaling. In collagen-induced arthritis (CIA) rat model, GLPG0634 significantly reduced the infiltration of inflammatory cells and reduced the levels of IL-6, IP-10, XCL1 and MCP-1 [1].

Reference:
[1].  Van Rompaey L, Galien R, van der Aar EM, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol, 2013, 191(7): 3568-3577.