Author: Amantini, David ; Jary, Hélène ; Mammoliti, Oscar ; López-Ramos, Miriam ; Desroy, Nicolas ; Nys, Kris ; Oste, Line ; Blanqué, Roland ; Komac, Marijana ; Bonnaterre, Florence ; Oršulić, Mislav ; Gosmini, Romain ; Borgonovi, Monica ; Wakselman, Emanuelle ; Newsome, Gregory ; Babel, Marielle ; Jimenez, Juan-Miguel ; De Lemos, Elsa ; Akkari, Rhalid ; Fernandes, Anna Pereira ; Brys, Reginald ; Kolb, Fabrice A ; Jagerschmidt, Catherine ; Vrban, Đenana ; Cherel, Laëtitia ; Trottet, Lionel

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.

12 Jun 2025·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4

Article

Author: Cottell, Jeromy J. ; Mwangi, Judy ; Bacon, Elizabeth M. ; Lansdon, Eric B. ; Dick, Ryan A. ; Brizgys, Gediminas ; Ammann, Stephen E. ; Chou, Chienhung ; Warr, Matthew R. ; Wright, Nathan E. ; Zipfel, Sheila M. ; Snyder, Chelsea A. ; Link, John O. ; Taylor, James G. ; Ndukwe, Marilyn S. ; Suekawa-Pirrone, Kimberly ; Mukherjee, Prasenjit Kumar ; Chin, Elbert ; Murray, Bernard P. ; Park, Grace Y. ; Hammond, Angela ; Garrison, Kimberly L. ; Yang, Zheng-Yu ; Ferrao, Ryan D. ; Conway, Angela ; Serone, Adrian P.

Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery of GS-5718 (edecesertib), a potent, selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor were efforts undertaken to improve the chemical series' profile after a significant hERG liability was encountered for an early compound. GS-5718 was safe and well-tolerated in IND-enabling preclinical animal toxicity studies, demonstrated efficacy in a mouse NZB lupus model, and additionally demonstrated human pharmacokinetic properties suitable for once-daily administration. Edecesertib is currently under clinical evaluation for the treatment of lupus.

01 Apr 2025·PHYTOMEDICINE

Apigenin alleviates inflammation as a natural IRAK4 inhibitor

Article

Author: Sun, Yili ; Kong, Lingmei ; Zhang, Yufei ; Ji, Kailong ; Gongpan, Pianchou ; Chen, Hongman ; Geng, Chang-An ; Xu, Tingting ; Li, Jia ; Wang, Xue ; Song, Qishi

BACKGROUND:

Uncontrolled inflammation is a key factor in the development of many diseases, and targeting pivotal kinases involved in the inflammatory response, such as interleukin-1 receptor-associated kinase 4 (IRAK4), holds promise for the treatment of inflammatory conditions. Apigenin (Api) is a popular element in numerous plants, possessing anti-inflammatory properties. Many studies have shown that Api modulates NF-κB signaling and MAPK cascade to reduce inflammation, but the exact mechanisms by which Api regulates these pathways remain unclear.

PURPOSE:

The aim of this study was to investigate the role of Api on acute inflammation and its specific mechanism in mediating inflammation.

METHODS:

The dextran sulfate sodium (DSS) induced ulcerative colitis (UC) model and LPS induced acute inflammation mouse model were established to investigate the anti-inflammatory effects of Api. Subsequently, the anti-inflammatory activity of Api was validated in vitro and vivo by RNA-seq, qPCR, Western blot, cytokine ELISA, immunofluorescence and histological analysis. A series of experiments were performed to study the effects of Api on IRAK4, including ADP-Glo™ kinase assay, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and molecular docking simulation. The targeting of Api to IRAK4 was verified by IRAK4 inhibitor and siRNA.

RESULTS:

Oral administration of Api significantly ameliorated inflammatory conditions in the LPS induced acute inflammation and DSS induced UC mouse models. Furthermore, Api inhibited the expression of interleukin and chemotactic factor genes and downregulated the immune response of macrophages at the transcriptome level. Mechanistically, Api acted as a novel IRAK4 inhibitor, inhibiting kinase activity by direct binding to IRAK4 (Kd = 4.78 μM) with an IC₅₀ of 1.74 μM, interfering with extracellular signaling to the NF-κB and MAPK pathways, and reducing the expression of pro-inflammatory factors in an IRAK4 dependent manner.

CONCLUSION:

In this study, Api was identified for the first time as a natural IRAK4 inhibitor that suppresses cytokine signaling pathways and modulates the immune response at the level of the transcriptome. The results provided valuable insights into the specific mechanism of Api inhibition of inflammatory activation and shed light on opportunities for the development of novel IRAK4 inhibitors based on Api, which is found in various plants.

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Indication	Highest Phase	Country/Location	Organization	Date
Immune System Diseases	Preclinical	China	Shanghai Xunhe Pharmaceutical Technology Co., Ltd	13 May 2022
Neoplasms	Preclinical	China	Shanghai Xunhe Pharmaceutical Technology Co., Ltd	13 May 2022

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