7t4j
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7t4j]] 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=7T4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T4J FirstGlance]. <br> | <table><tr><td colspan='2'>[[7t4j]] 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=7T4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T4J FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=R28:propan-2-yl+2-[[4-[2-(dimethylamino)ethyl-methyl-amino]-2-methoxy-5-(propanoylamino)phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate'>R28</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=R28:propan-2-yl+2-[[4-[2-(dimethylamino)ethyl-methyl-amino]-2-methoxy-5-(propanoylamino)phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate'>R28</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=7t4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t4j OCA], [https://pdbe.org/7t4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t4j RCSB], [https://www.ebi.ac.uk/pdbsum/7t4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t4j 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=7t4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t4j OCA], [https://pdbe.org/7t4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t4j RCSB], [https://www.ebi.ac.uk/pdbsum/7t4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t4j ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. | In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. | ||
| - | Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.,Huang WS, Li F, Gong Y, Zhang Y, Youngsaye W, Xu Y, Zhu X, Greenfield MT, Kohlmann A, Taslimi PM, Toms A, Zech SG, Zhou T, Das B, Jang HG, Tugnait M, Ye YE, Gonzalvez F, Baker TE, Nadworny S, Ning Y, Wardwell SD, Zhang S, Gould AE, Hu Y, Lane W, Skene RJ, Zou H, Clackson T, Narasimhan NI, Rivera VM, Dalgarno DC, Shakespeare WC Bioorg Med Chem Lett. | + | Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.,Huang WS, Li F, Gong Y, Zhang Y, Youngsaye W, Xu Y, Zhu X, Greenfield MT, Kohlmann A, Taslimi PM, Toms A, Zech SG, Zhou T, Das B, Jang HG, Tugnait M, Ye YE, Gonzalvez F, Baker TE, Nadworny S, Ning Y, Wardwell SD, Zhang S, Gould AE, Hu Y, Lane W, Skene RJ, Zou H, Clackson T, Narasimhan NI, Rivera VM, Dalgarno DC, Shakespeare WC Bioorg Med Chem Lett. 2023 Jan 15;80:129084. doi: 10.1016/j.bmcl.2022.129084. , Epub 2022 Nov 21. PMID:36423823<ref>PMID:36423823</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7t4j" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7t4j" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal Structure of EGFR_D770_N771insNPG/V948R in complex with TAK-788
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Categories: Homo sapiens | Large Structures | Hu Y | Lane W | Skene RJ
