Abstract Janus kinase inhibitors have demonstrated efficacy in treating inflammatory and autoimmune diseases; however, several concerns restrict their use in medical practice. One member of this kinase family, tyrosine kinase 2 (TYK2), recently attracted attention owing to the limited number of key inflammatory cytokine pathways it mediates (type I interferon, interleukin IL-12/IL-23, and IL-10 family pathways) and the numerous genetic studies associating polymorphisms of the TYK2 gene with protection against several inflammatory and autoimmune diseases. In that regard, we discovered a selective, reversible, ATP-competitive inhibitor of TYK2, GLPG3667. We present the selectivity of GLPG3667 in biochemical, cellular, and human whole blood assays. In vitro, GLPG3667 inhibited the IL-12- and IL-23-induced polarization of T helper (T H )1 and T H 17, respectively, but was shown to have a more limited impact on the IL-10 pathway and the anti-inflammatory effects of IL-10 in vitro. Pharmacodynamic analyses performed during phase 1 trials, in which healthy volunteers received GLPG3667 orally, confirmed the selectivity of the compound for TYK2-dependent pathways. In addition, following an in vivo challenge in these healthy volunteers, GLPG3667 inhibited the biological effects of interferon-α, supporting its potential use in treating several inflammatory and autoimmune diseases.
Cottereaux et al. (Sat,) studied this question.
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