Kinases typically integrate signaling events down-stream of multiple cytokine receptors. Hence, kinase inhibitors distinguish themselves from cytokine-targeted biologicals by their capacity to modulate multiple signaling pathways simultaneously. IL-1 receptor (IL-1R)–associated kinase 4 (IRAK4) is a kinase that is located at the intersection of signaling pathways. Of particular interest, IRAK4 and IRAK4-dependent pathways are active both in cells involved in adaptive immune responses and in nonhemopoietic cell types. In view of the central role of IRAK4 in immune pathways, we will introduce an IRAK4 Inhibitor–GLPG2534.
GLPG2534 is an Orally Active IRAK4 Inhibitor.
GLPG2534 has low nanomolar IC50 for IRAK4, with IC50 values of 6.4 nM and 3.5 nM for human and mouse IRAK4. In addition, GLPG2534 shows good biological activity in vivo and in vitro experiments.
In vitro experiments, GLPG2534 (0.1-10 μM, 16 h) inhibits expression of S100A7, DEFB4A, CXCL8, and TNF in Flagellin-stimulated keratinocytes. GLPG2534 also inhibits IL-1β–driven IL-6 release, with an IC50 of 55 nM. Moreover, GLPG2534 inhibits TNF-α–driven IL-6 release with an IC50 of 6.6 μM.
In vivo, GLPG2534 (0.3-10 mg/kg, p.o.) Inhibits CL097-driven release of TNF-α in the blood of mice. In addition, GLPG2534 (10 and 30 mg/kg, p.o., b.i.d. 5 days) attenuates inflammation in psoriasis-like mouse models. Moreover, GLPG2534 (3-30 mg/kg, p.o., b.i.d. 5 days) attenuates the development of IL-33- and MC903-induced AD-like skin inflammation in mice.
Increasing evidence suggests that targeting IRAK4 is an attractive therapeutic concept for several immune-mediated inflammatory diseases (IMIDs). A first strong indicator is the association of polymorphisms for genes located on IRAK4 pathways with multiple IMIDs, such as IRAK1 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). As a second piece of evidence, preclinical studies performed with IRAK4-deficient mice suggested the therapeutic potential of IRAK4 inhibition in diseases as RA, SLE, and multiple sclerosis.
Hence, as an IRAK4 Inhibitor, GLPG2534 is a promising agent.