Journal of medicinal chemistry · 2024
Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases.
СтатьяКлиническое исследование I фазыПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Mammoliti Oscar, Martina Sébastien, Claes Pieter, Coti Ghjuvanni, Blanque Roland, Jagerschmidt Catherine, Shoji Kenji, Borgonovi Monica, De Vos Steve, Marsais Florence, Oste Line, Quinton Evelyne, López-Ramos Miriam, Amantini David, Brys Reginald, Jimenez Juan-Miguel, Galien René, van der Plas Steven
Аннотация
Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).