View source for 8ucc


==IRAK4 in complex with compound 20==
<StructureSection load='8ucc' size='340' side='right'caption='[[8ucc]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ucc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UCC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UCC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=WFQ:2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-~{N}-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)-7-propan-2-yloxy-imidazo[1,2-a]pyrimidine-6-carboxamide'>WFQ</scene></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=8ucc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ucc OCA], [https://pdbe.org/8ucc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ucc RCSB], [https://www.ebi.ac.uk/pdbsum/8ucc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ucc ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke.,Evans R, Bolduc PN, Pfaffenbach M, Gao F, May-Dracka T, Fang T, Hopkins BT, Chodaparambil JV, Henry KL, Li P, Metrick C, Nelson A, Trapa P, Thomas A, Burkly L, Peterson EA J Med Chem. 2024 Mar 28;67(6):4676-4690. doi: 10.1021/acs.jmedchem.3c02226. Epub , 2024 Mar 11. PMID:38467640<ref>PMID:38467640</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ucc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chodaparambil JV]]
[[Category: Metrick CM]]