8br7

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Current revision (09:46, 9 October 2024) (edit) (undo)
 
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8br7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8br7 OCA], [https://pdbe.org/8br7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8br7 RCSB], [https://www.ebi.ac.uk/pdbsum/8br7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8br7 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8br7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8br7 OCA], [https://pdbe.org/8br7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8br7 RCSB], [https://www.ebi.ac.uk/pdbsum/8br7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8br7 ProSAT]</span></td></tr>
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== Disease ==
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<div style="background-color:#fffaf0;">
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[https://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:[https://omim.org/entry/610799 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.<ref>PMID:16950813</ref> Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:[https://omim.org/entry/607676 607676]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.<ref>PMID:12925671</ref> <ref>PMID:12637671</ref>
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== Publication Abstract from PubMed ==
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== Function ==
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Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.
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[https://www.uniprot.org/uniprot/IRAK4_HUMAN 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.<ref>PMID:11960013</ref> <ref>PMID:12538665</ref> <ref>PMID:15084582</ref> <ref>PMID:17217339</ref> <ref>PMID:17337443</ref> <ref>PMID:17997719</ref> <ref>PMID:20400509</ref>
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Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.,Bothe U, Gunther J, Nubbemeyer R, Siebeneicher H, Ring S, Bomer U, Peters M, Rausch A, Denner K, Himmel H, Sutter A, Terebesi I, Lange M, Wengner AM, Guimond N, Thaler T, Platzek J, Eberspacher U, Schafer M, Steuber H, Zollner TM, Steinmeyer A, Schmidt N J Med Chem. 2024 Jan 25;67(2):1225-1242. doi: 10.1021/acs.jmedchem.3c01714. Epub , 2024 Jan 16. PMID:38228402<ref>PMID:38228402</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8br7" style="background-color:#fffaf0;"></div>
== References ==
== References ==
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Current revision

Discovery of IRAK4 Inhibitors BAY1834845 and BAY1830839

PDB ID 8br7

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