Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzofuran IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma

Chen, Yun; Ning, Yi; Chen, Zhiwei; Xue, Yunfei; Wu, Qingyun; Duan, Wenhu; Ding, Jian; Zhou, Jinpei; Xie, Hua; Zhang, Huibin

doi:10.1016/j.ejmech.2023.115453

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Therefore, we aimed to develop a novel IRAK4 inhibitor to combat inflammatory diseases. We have developed a series of IRAK4 inhibitors bearing an oxazole-4carboxamide scaffold via structure-based drug design (SBDD) [26], among which DW18134 outperformed its counterparts as a potent and selective IRAK4 inhibitor (Figure 1A). The enzymatic activity assay demonstrated that DW18134 effectively inhibited IRAK4, with an IC 50 value of 11.2 nM, which was less potent than that of positive control compound PF-06650833 (…”

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

confidence: 99%

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

confidence: 99%

“…Compound DW18134 was designed and synthesized by Dr. Wenhu Duan's laboratory [26]. PF-06650833 was purchased from MedChemExpress (#HY-19836, Princeton, NJ, USA).…”

Section: Compoundsmentioning

confidence: 99%