Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome

Li, Qianqian; Li, Rui; Yin, Hanlin; Wang, Suli; Liu, Bei; Li, Jun; Zhou, Mi; Yan, Qingran; Lu, Liangjing

doi:10.1016/j.biopha.2022.113459

Cited by 11 publications

(13 citation statements)

References 66 publications

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“…Interestingly, very recent reports have indicated that SARS-CoV-2 could modulate IRAKs signaling pathway. For example, direct inhibition of IRAK4 has been shown to prevent SARS-CoV-2-mediated acute respiratory distress syndrome in mouse models [ 80 ]. Also, IRAK4 dysregulation by small interfering RNA has been reported to obstruct the SARS-CoV-2-induced cytotoxic effect in vitro [ 81 ].…”

Section: Iraks/nf-κb/ap1 Could Be the Major Pathway That Regulates Sa...mentioning

confidence: 99%

“…Therefore, IRAK1 and IRAK4 have been the focus of multiple drug development platforms and recently advanced to clinical studies for various types of disorders particularly inflammatory diseases [ 100 , 101 ]. Since COVID-19 is an inflammatory disease associated with induction of cytokine release, inhibition of IRAK proteins can reduce the high release of cytokines and hence reduce the respiratory distress syndrome [ 80 ]. Some of IRAK inhibitors are still in preclinical stages, others are already in clinical trials for the treatment of different diseases, including cancers and rheumatoid arthritis [ 102 ].…”

Section: Targeting Iraks Represents An Attractive Strategy To Counter...mentioning

confidence: 99%

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Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

2023

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients.

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Section: Iraks/nf-κb/ap1 Could Be the Major Pathway That Regulates Sa...mentioning

confidence: 99%

Section: Targeting Iraks Represents An Attractive Strategy To Counter...mentioning

confidence: 99%

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

2023

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“…For instance, Yoon et al used oral doses of PF-06650833 at 50 and 100 mg kg −1 to treat LPS-mediated systemic inflammation in mice, [45] while Li et al administered an oral dose of 100 mg kg −1 to mice with acute respiratory distress syndrome. [46] On day 10, mice were euthanized, their entire colons were excised, and colon length reduction was assessed as a key indicator of the severity of DSS-induced colitis. [47] The average colon length of healthy mice was 6.35 ± 0.16 cm, whereas this parameter decreased significantly to 5.44 ± 0.55 cm in animals with 7a,b).…”

Section: In Vivo Evaluation Of Vcam1-irak4 Nc In Mice With Dss-induce...mentioning

confidence: 99%

Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues

Park,

Korzun,

Moses

et al. 2023

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Persistent and uncontrolled inflammation is the root cause of various debilitating diseases. Given that interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical modulator of inflammation, inhibition of its activity with selective drug molecules (IRAK4 inhibitors) represents a promising therapeutic strategy for inflammatory disorders. To exploit the full potential of this treatment approach, drug carriers for efficient delivery of IRAK4 inhibitors to inflamed tissues are essential. Herein, the first nanoparticle‐based platform for the targeted systemic delivery of a clinically tested IRAK4 inhibitor, PF‐06650833, with limited aqueous solubility (57 µg mL−1) is presented. The developed nanocarriers increase the intrinsic aqueous dispersibility of this IRAK4 inhibitor by 40 times. A targeting peptide on the surface of nanocarriers significantly enhances their accumulation after intravenous injection in inflamed tissues of mice with induced paw edema and ulcerative colitis when compared to non‐targeted counterparts. The delivered IRAK4 inhibitor markedly abates inflammation and dramatically suppresses paw edema, mitigates colitis symptoms, and reduces proinflammatory cytokine levels in the affected tissues. Importantly, repeated injections of IRAK4 inhibitor‐loaded nanocarriers have no acute toxic effect on major organs of mice. Therefore, the developed nanocarriers have the potential to significantly improve the therapeutic efficacy of IRAK4 inhibitors for different inflammatory diseases.

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“…Phosphorylated IRAK4 further induces IRAK1 phosphorylation and mediates downstream inflammatory signaling via multiple cascades. Several IRAK4 inhibitors, including PF-06650833, BAY-1830839, zabedosertib, edecesertib, and emavusertib, are currently undergoing clinical trials (Figure C).…”

Section: Introductionmentioning

confidence: 99%

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases

Chen,

Luo,

et al. 2024

J. Med. Chem.

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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

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Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome

Cited by 11 publications

References 66 publications

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases

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