View source for 7qg1


==IRAK4 in complex with inhibitor==
<StructureSection load='7qg1' size='340' side='right'caption='[[7qg1]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QG1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QG1 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]] 2.07&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B8I:methyl+4-[4-[[6-(cyanomethyl)-2-[(1-methylpyrazol-4-yl)amino]-5-oxidanylidene-pyrido[4,3-d]pyrimidin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate'>B8I</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=7qg1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qg1 OCA], [https://pdbe.org/7qg1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qg1 RCSB], [https://www.ebi.ac.uk/pdbsum/7qg1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qg1 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.

Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.,Cumming IA, Degorce SL, Aagaard A, Braybrooke EL, Davies NL, Diene CR, Eatherton AJ, Felstead HR, Groombridge SD, Lenz EM, Li Y, Nai Y, Pearson S, Robb GR, Scott JS, Steward OR, Wu C, Xue Y, Zhang L, Zhang Y Bioorg Med Chem. 2022 Jun 1;63:116729. doi: 10.1016/j.bmc.2022.116729. Epub 2022 , Apr 2. PMID:35439688<ref>PMID:35439688</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qg1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Aagaard A]]
[[Category: Degorce SL]]
[[Category: Robb GR]]
[[Category: Xue Y]]