ArticleThe Journal of experimental medicine2015
Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.
Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
82 citing papers in PubMed, 155 citations in OpenAlex.
- The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers.Clinical and translational science · 2024Trial
- The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.Arthritis & rheumatology (Hoboken, N.J.) · 2021Trial
- Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.Arthritis research & therapy · 2019Trial
- Familial lymphoma and genetic predisposition: an updated review.BMC medical genomics · 2026Review
- Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.Acta pharmaceutica Sinica. B · 2024Review
- Research progress on the mechanism of common inflammatory pathways in the pathogenesis and development of lymphoma.Annals of medicine · 2024Review
- Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs.British journal of pharmacology · 2024Article
- Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice.Arthritis research & therapy · 2024Article
- A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.Molecules (Basel, Switzerland) · 2024Article
- TGFA expression is associated with poor prognosis and promotes the development of cervical cancer.Journal of cellular and molecular medicine · 2024Article
- Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm.Clinical and experimental medicine · 2023Review
- A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-Acta pharmaceutica Sinica. B · 2023Article
- Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors.Journal of clinical medicine · 2023Article
- IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies.Frontiers in immunology · 2023Review
- Drug Repositioning Applied to Cardiovascular Disease in Mucopolysaccharidosis.Life (Basel, Switzerland) · 2022Article
- Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Article
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Cell & bioscience · 2022Review
- Review
- Discovery of 5-Aryl-2,4-diaminopyrimidine Compounds as Potent and Selective IRAK4 Inhibitors.ACS medicinal chemistry letters · 2022Article
- Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors.Nature communications · 2022Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.