8dks

IRAK4 IN COMPLEX WITH COMPOUND #3

spinqualitylabelsall models 8dks, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dks is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BME, SEP, SO9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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. 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. Publication Abstract from PubMed Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1beta induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies. Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.,Chen Y, Tso K, Heckrodt TJ, Li H, Yen R, Lin N, Singh R, Taylor V, Masuda ES, Park G, Payan DG Bioorg Med Chem Lett. 2022 Jul 18:128900. doi: 10.1016/j.bmcl.2022.128900. PMID:35863718 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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