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

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-23 DOI:10.1016/j.bmcl.2025.130386

Oscar Mammoliti , Florence Bonnaterre , Gregory Newsome , Rhalid Akkari , Miriam López-Ramos , Marielle Babel , Hélène Jary , Laëtitia Cherel , Elsa De Lemos , Mislav Oršulić , Marijana Komac , Đenana Vrban , Lionel Trottet , Line Oste , Emanuelle Wakselman , Monica Borgonovi , Catherine Jagerschmidt , Anna Pereira Fernandes , Roland Blanqué , Kris Nys , Nicolas Desroy

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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.

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发现GLPG4471，一种有效的选择性IRAK4抑制剂，用于治疗炎症和自身免疫性疾病。

白细胞介素-1受体相关激酶4 （IRAK4）是通过toll样受体和白细胞介素-1受体信号通路分泌细胞因子和干扰素的关键介质。已经研究了IRAK4活性的调节，以治疗炎症和自身免疫性疾病以及恶性肿瘤。在这里，从高通量筛选活动中鉴定出新的IRAK4抑制剂。旨在提高IRAK4效价和亲脂效率的初步构效关系研究。然后，对结构进行修饰，以增加在肝细胞中孵育时对酰胺裂解的稳定性，并减少人类醚-a-go-go相关基因（hERG）的抑制。通过对吸收、分布、代谢、排泄和毒性（ADMET）特性的优化，化合物21 （GLPG4471）是一种有效的IRAK4抑制剂，在对369种激酶的测试中表现出优异的选择性。在细胞和全血表型分析中，化合物21显示出对细胞因子分泌的有效抑制。化合物21在小鼠体内胶原诱导关节炎模型中显示出剂量依赖性活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.