6o95

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Current revision (08:11, 17 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=6o95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o95 OCA], [https://pdbe.org/6o95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o95 RCSB], [https://www.ebi.ac.uk/pdbsum/6o95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o95 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=6o95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o95 OCA], [https://pdbe.org/6o95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o95 RCSB], [https://www.ebi.ac.uk/pdbsum/6o95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o95 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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A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.
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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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Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.,Bryan MC, Drobnick J, Gobbi A, Kolesnikov A, Chen Y, Rajapaksa N, Ndubaku C, Feng J, Chang W, Francis R, Yu C, Choo EF, DeMent K, Ran Y, An L, Emson C, Huang Z, Sujatha-Bhaskar S, Brightbill H, DiPasquale A, Maher J, Wai J, McKenzie BS, Lupardus PJ, Zarrin AA, Kiefer JR J Med Chem. 2019 May 24. doi: 10.1021/acs.jmedchem.9b00439. PMID:31082230<ref>PMID:31082230</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>
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<div class="pdbe-citations 6o95" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==

Current revision

Structure of the IRAK4 kinase domain with compound 41

PDB ID 6o95

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

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