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9h47
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==EGFR wild type in complex with 26313== | |
| + | <StructureSection load='9h47' size='340' side='right'caption='[[9h47]], [[Resolution|resolution]] 2.99Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9h47]] is a 1 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=9H47 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9H47 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]] 2.991Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IR9:2-[[4-[2-(dimethylamino)ethyl-methyl-amino]phenyl]amino]-8-phenyl-pyrido[2,3-d]pyrimidin-7-one'>A1IR9</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=9h47 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9h47 OCA], [https://pdbe.org/9h47 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9h47 RCSB], [https://www.ebi.ac.uk/pdbsum/9h47 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9h47 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inhibitors of epidermal growth factor receptor (EGFR) kinase activity are clinically effective treatments for lung cancers driven by activating mutations in EGFR. Resistance to inhibitors develops over time, frequently through further mutations in the kinase domain. On-target resistance to third-generation inhibitor osimertinib, commonly develops through C797S mutation that prevents covalent binding. There is an urgent need for new treatments for osimertinib-resistant EGFR mutants that retain the advantages of the covalent mechanism. Compounds were designed and synthesized to covalently inhibit EGFR through C775, a further cysteine residue we identified in the orthosteric site. Optimisation of the alkynylpyridopyrimidinone scaffold we discovered led to potent compounds that demonstrate inhibition of EGFR phosphorylation and tumor growth in all EGFR mutant cell lines. The covalent C775 mode-of-action was comprehensively established. This work demonstrates that covalent targeting of C775 is a viable mechanism for the treatment of pan-EGFR mutated cancers, particularly those resistant to current therapies. | ||
| - | + | Covalent Alkynylpyridopyrimidinones Targeting Cysteine 775 of the Epidermal Growth Factor Receptor Overcome Resistance to Current Therapies.,Stewart HL, Bordoni C, Jennings CE, Al-Khawaldeh I, Martin MP, Noble RA, Phillips N, Pintar S, Prendergast L, Thomas HD, Wang LZ, Watt JE, Wittner A, Bronowska AK, Cano C, Noble MEM, Wedge SR, Waring MJ J Med Chem. 2026 Jan 8;69(1):533-552. doi: 10.1021/acs.jmedchem.5c02924. Epub , 2025 Dec 23. PMID:41432179<ref>PMID:41432179</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9h47" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Martin MP]] | ||
| + | [[Category: Noble MEM]] | ||
| + | [[Category: Pintar S]] | ||
Current revision
EGFR wild type in complex with 26313
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