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From Proteopedia
IRAK4 IN COMPLEX WITH inhibitor
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 PubMedIn this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor which proved efficacious in combination with ibrutinib, whilst showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents, and was attributed to the enhanced specificity of 13 towards IRAK4. Discovery of a series of 5-AzaQuinazolines as orally efficacious IRAK4 inhibitors targeting MyD88L265P mutant Diffuse Large B Cell Lymphoma.,Degorce SL, Anjum R, Bloecher A, Carbajo RJ, Dillman K, Drew L, Halsall CT, Lenz EM, Lindsay NA, Mayo M, Pink J, Robb GR, Rosen A, Scott JS, Xue Y J Med Chem. 2019 Oct 17. doi: 10.1021/acs.jmedchem.9b01346. PMID:31622099[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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