IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase
TLDR
IRAK-4 is the closest human homolog to Pelle and depends on its kinase activity to activate NF-κB, suggesting a role of IRAK- 4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAk-1.Abstract:
Toll/IL-1 receptor family members are central components of host defense mechanisms in a variety of species. One well conserved element in their signal transduction is Ser/Thr kinases, which couple early signaling events in a receptor complex at the plasma membrane to larger signalosomes in the cytosol. The fruit fly Drosophila melanogaster has one member of this family of kinases, termed Pelle. The complexity of this pathway is vastly increased in vertebrates, and several Pelle homologs have been described and termed IL-1 receptor-associated kinase (IRAK). Here we report the identification of a novel and distinct member of the IRAK family, IRAK-4. IRAK-4 is the closest human homolog to Pelle. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner, and overexpression of IRAK-4 can activate NF-κB as well as mitogen-activated protein (MAP) kinase pathways. Most strikingly, and in contrast to the other IRAKs, IRAK-4 depends on its kinase activity to activate NF-κB. In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.read more
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Patent
Aminopyrimidinones as interleukin receptor-associated kinase inhibitors
W. Michael Seganish,Stephanie Brumfield,Jongwon Lim,Julius J. Matasi,William T. McElroy,Deen Tulshian,Brian J. Lavey,Michael D. Altman,Craig R. Gibeau,John William Lampe,Joey L. Methot,Liang Zhu +11 more
TL;DR: Aminopyrimidinone compounds of Formula (I) are inhibitors of Interleukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment or prevention of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease.
Journal ArticleDOI
Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.
Graham Smith,Michael D. Altman,Brian M. Andresen,James Baker,Jason D. Brubaker,Hongmin Chen,Yiping Chen,Matthew Lloyd Childers,Anthony Donofrio,Heidi Ferguson,Christian Fischer,Thierry O. Fischmann,Craig R. Gibeau,Alexander Hicks,Sue Jin,Sam Kattar,Melanie A. Kleinschek,Erica Leccese,Charles A. Lesburg,Chaomin Li,Jongwon Lim,Duan Liu,John Maclean,Faruk Mansoor,Lilly Y. Moy,Erin F. Mulrooney,Antoaneta S. Necheva,Jeremy Presland,Larissa Rakhilina,Ruojing Yang,Luis E. Torres,Jie Zhang-Hoover,Alan B. Northrup +32 more
TL;DR: High throughput screening hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity.
Book ChapterDOI
Small Molecule Inhibition of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4)
N E Genung,K M Guckian +1 more
TL;DR: Within this review, the considerable effort by numerous groups dedicated to the development of small molecule IRAK4 inhibitors for the treatment of human disease is highlighted.
Journal ArticleDOI
Contribution of globular death domains and unstructured linkers to MyD88·IRAK-4 heterodimer formation: An explanation for the antagonistic activity of MyD88s
Elena Mendoza-Barberá,María Ángeles Corral-Rodríguez,Alessandra Soares-Schanoski,Milko Velarde,Sofia Macieira,Albrecht Messerschmidt,Eduardo López-Collazo,Pablo Fuentes-Prior +7 more
TL;DR: These findings indicate that residues 110-120, which form a C-terminal extra helix in MyD88, but not the irregular linker between DD and TIR domains, are required for IRAK-4 recruitment, and provide a straightforward explanation for the negative regulation of innate immune responses mediated by MyD 88s.
Journal ArticleDOI
A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice
TL;DR: It is demonstrated that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-κB activation in this model organism, and that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways.
References
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