2. Academic Validation
  3. Discovery of GLPG4471, a potent and selective IRAK4 inhibitor for the treatment of inflammatory and autoimmune diseases

Discovery of GLPG4471, a potent and selective IRAK4 inhibitor for the treatment of inflammatory and autoimmune diseases

  • Bioorg Med Chem Lett. 2025 Dec 15:129:130386. doi: 10.1016/j.bmcl.2025.130386.
Oscar Mammoliti 1,  Florence Bonnaterre 1,  Gregory Newsome 1,  Rhalid Akkari 1,  Miriam López-Ramos 1,  Marielle Babel 1,  Hélène Jary 1,  Laëtitia Cherel 1,  Elsa De Lemos 1,  Mislav Oršulić 2,  Marijana Komac 2,  Đenana Vrban 2,  Lionel Trottet 1,  Line Oste 3,  Emanuelle Wakselman 1,  Monica Borgonovi 1,  Catherine Jagerschmidt 1,  Anna Pereira Fernandes 3,  Roland Blanqué 1,  Kris Nys 3,  Fabrice A Kolb 4,  Reginald Brys 3,  David Amantini 1,  Romain Gosmini 1,  Juan-Miguel Jimenez 3,  Nicolas Desroy 5
Affiliations

Affiliations

  • 1 Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Selvita, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia.
  • 3 Galapagos NV, Generaal-De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 4 Galapagos GmbH, Aeschengraben 27, 4051 Basel, Switzerland.
  • 5 Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France. Electronic address: ndesroy.consulting@gmail.com.
PMID: 40854432 DOI: 10.1016/j.bmcl.2025.130386
Abstract

Interleukin-1 receptor associated kinase 4 (IRAK4) is a key mediator of the secretion of cytokines and interferons via Toll-like Receptor and interleukin-1 receptor signaling pathways. Modulation of IRAK4 activity has been investigated for the treatment of inflammatory and autoimmune diseases and of malignancies. Here, new IRAK4 inhibitors were identified from a high throughput screening campaign. Initial structure-activity relationship efforts aimed at improving potency and lipophilic efficiency on IRAK4. Then, structural modifications were made to increase stability towards amide cleavage upon incubation in hepatocytes, and to decrease human ether-a-go-go related gene (hERG) inhibition. Optimization of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties led to compound 21 (GLPG4471), a potent IRAK4 Inhibitor that showed excellent selectivity when tested against a panel of 369 kinases. Compound 21 exhibited potent inhibition of cytokine secretion in cellular and whole blood phenotypic assays. Compound 21 displayed dose-dependent activity in vivo in a mouse model of collagen-induced arthritis.

Keywords

Collagen-induced arthritis; IRAK4; Inflammation; Kinase inhibitor.

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