View source for 8tvn


==IRAK4 in complex with compound 23==
<StructureSection load='8tvn' size='340' side='right'caption='[[8tvn]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tvn]] is a 4 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=8TVN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TVN 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]] 1.95&#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=VE9:~{N}-[1-[(1~{S},2~{R})-2-fluoranylcyclopropyl]-2-oxidanylidene-pyridin-3-yl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-6-propan-2-yloxy-pyrazolo[3,4-b]pyridine-5-carboxamide'>VE9</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=8tvn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tvn OCA], [https://pdbe.org/8tvn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tvn RCSB], [https://www.ebi.ac.uk/pdbsum/8tvn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tvn ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.,Bolduc PN, Pfaffenbach M, Evans R, Xin Z, Henry KL, Gao F, Fang T, Silbereis J, Vera Rebollar J, Li P, Chodaparambil JV, Metrick C, Peterson EA ACS Med Chem Lett. 2024 Apr 26;15(5):714-721. doi: , 10.1021/acsmedchemlett.4c00102. eCollection 2024 May 9. PMID:38746903<ref>PMID:38746903</ref>

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