Scholarlink

<p>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 <i>TYK2</i> 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<sub>H</sub>)1 and T<sub>H</sub>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Pharmacological Characterization of GLPG3667, a Tyrosine Kinase 2-Selective Inhibitor, for the Treatment of Inflammatory and Autoimmune Diseases

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月16日

查看全文
  • Céline Cottereaux,
  • May-Linda Lepage,
  • Isabelle Parent,
  • Maikel Colli,
  • An Van de Water,
  • Emilie Lagoutte,
  • Christelle David,
  • Maarten Van Balen,
  • Adrien Cosson,
  • Roland Blanque,
  • Kenji Shoji,
  • Mia Jans,
  • Laetitia Furio,
  • Steven Van der Plas,
  • Reginald Brys,
  • David Amantini,
  • René Galien

摘要

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 (TH)1 and TH17, 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.