8a27 - Revision history

OCA at 13:36, 1 February 2024

OCA — Thu, 01 Feb 2024 13:36:13 GMT

←Older revision		Revision as of 13:36, 1 February 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8a27]] 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=8A27 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A27 FirstGlance]. <br>		<table><tr><td colspan='2'>[[8a27]] 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=8A27 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A27 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KY9:(2R)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[5-[2-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]phenyl]ethynyl]-3-oxidanylidene-7-(trifluoromethyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)ethanamide'>KY9</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 1.07Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KY9:(2R)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[5-[2-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]phenyl]ethynyl]-3-oxidanylidene-7-(trifluoromethyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)ethanamide'>KY9</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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=8a27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a27 OCA], [https://pdbe.org/8a27 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a27 RCSB], [https://www.ebi.ac.uk/pdbsum/8a27 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a27 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=8a27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a27 OCA], [https://pdbe.org/8a27 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a27 RCSB], [https://www.ebi.ac.uk/pdbsum/8a27 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a27 ProSAT]</span></td></tr>
	</table>		</table>
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	</div>		</div>
	<div class="pdbe-citations 8a27" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 8a27" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 19:25, 19 October 2022

OCA — Wed, 19 Oct 2022 19:25:51 GMT

←Older revision		Revision as of 19:25, 19 October 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 8a27 is ~~ON HOLD until Paper~~ Publication	+	==EGFR kinase domain in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide==
		+	<StructureSection load='8a27' size='340' side='right'caption='[[8a27]], [[Resolution\|resolution]] 1.07Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8a27]] 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=8A27 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A27 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KY9:(2R)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[5-[2-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]phenyl]ethynyl]-3-oxidanylidene-7-(trifluoromethyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)ethanamide'>KY9</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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=8a27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a27 OCA], [https://pdbe.org/8a27 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a27 RCSB], [https://www.ebi.ac.uk/pdbsum/8a27 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a27 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 ==
		+	Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR(C797S) mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFR(C797S)-mediated resistance in patients harboring the activating EGFR(L858R) mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR(L858R/C797S) tumor model. Additionally, 57 is active in an H1975 EGFR(L858R/T790M) NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFR(L858R/C797S) and EGFR(L858R/T790M/C797S) and as combination therapy for EGFR(L858R)- and EGFR(L858R/T790M)-driven NSCLC.

-	~~Authors~~:	+	Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.,Obst-Sander U, Ricci A, Kuhn B, Friess T, Koldewey P, Kuglstatter A, Hewings D, Goergler A, Steiner S, Rueher D, Imhoff MP, Raschetti N, Marty HP, Dietzig A, Rynn C, Ehler A, Burger D, Kornacker M, Schaffland JP, Herting F, Pao W, Bischoff JR, Martoglio B, Alice Nagel Y, Jaeschke G J Med Chem. 2022 Oct 13;65(19):13052-13073. doi: 10.1021/acs.jmedchem.2c00893., Epub 2022 Sep 30. PMID:36178776<ref>PMID:36178776</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8a27" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Ehler A]]
		+	[[Category: Kuglstatter A]]

OCA at 07:16, 22 June 2022

OCA — Wed, 22 Jun 2022 07:16:33 GMT

←Older revision		Revision as of 07:16, 22 June 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8a27 is ON HOLD	+	The entry 8a27 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8a27" [edit=sysop:move=sysop]

OCA — Wed, 08 Jun 2022 04:24:17 GMT

Protected "8a27" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:24, 8 June 2022

OCA: New page: '''Unreleased structure''' The entry 8a27 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 08 Jun 2022 04:24:16 GMT

New page: '''Unreleased structure''' The entry 8a27 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8a27 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]