A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo

Choudhary, Saynaz A.; Patra, Debarun; Sinha, Archana; Mazumder, Sayani; Pant, Rajat; Chouhan, Raju; Jha, Anupam Nath; Prusty, Biswamohan; Manna, Debasis; Das, Sajal; Tikoo, Kulbhushan; Pal, Durba; Dasgupta, Suman

doi:10.1016/j.ejphar.2023.175593

Cited by 5 publications

(2 citation statements)

References 60 publications

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“…Total protein isolation from in vitro studies was performed following studies performed earlier by the group ( 46 ). Briefly, cells were lysed and centrifuged at 13,0000 rpm for 10 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Adipose tissue macrophage–derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity

Patra,

Ramprasad,

Sharma

et al. 2024

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Adipose tissue macrophage–derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity

Patra,

Ramprasad,

Sharma

et al. 2024

Journal of Biological Chemistry

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“…IRAK4 kinase has been reported to be closely associated with inflammatory and autoimmune diseases, and several IRAK4 inhibitors have been used in the study of such disorders [23][24][25]. Therefore, we aimed to develop a novel IRAK4 inhibitor to combat inflammatory diseases.…”

Section: Dw18134 Potently Inhibited Irak4 Kinase Activity and Attenua...mentioning

confidence: 99%

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease

Huang,

Ning,

Chen

et al. 2024

Molecules

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IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

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Targeting MAPK-ERK/JNK pathway: A potential intervention mechanism of myocardial fibrosis in heart failure

Zhang,

Yang,

Wang

et al. 2024

Biomedicine & Pharmacotherapy

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A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo

Cited by 5 publications

References 60 publications

Adipose tissue macrophage–derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity

Adipose tissue macrophage–derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease

Targeting MAPK-ERK/JNK pathway: A potential intervention mechanism of myocardial fibrosis in heart failure

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