5t1t
From Proteopedia
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| - | ==See Also== | ||
| - | *[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]] | ||
== References == | == References == | ||
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Revision as of 12:51, 6 November 2017
Irak4 kinase - compound 1 co-structure
Structural highlights
Disease[IRAK4_HUMAN] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.[1] Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.[2] [3] Function[IRAK4_HUMAN] Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.[4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedInterleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) 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. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation. Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.,Smith GF, Altman MD, Andresen B, Baker J, Brubaker JD, Chen H, Chen Y, Childers M, Donofrio A, Ferguson H, Fischer C, Fischmann TO, Gibeau C, Hicks A, Jin S, Kattar S, Kleinschek MA, Leccese E, Lesburg C, Li C, Lim J, Liu D, Maclean JKF, Mansoor F, Moy LY, Mulrooney EF, Necheva AS, Presland J, Rakhilina L, Yang R, Torres L, Zhang-Hoover J, Northrup A Bioorg Med Chem Lett. 2017 Jun 15;27(12):2721-2726. doi:, 10.1016/j.bmcl.2017.04.050. Epub 2017 Apr 18. PMID:28501511[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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