7jxq - Revision history

OCA at 15:14, 18 October 2023

OCA — Wed, 18 Oct 2023 15:14:06 GMT

←Older revision		Revision as of 15:14, 18 October 2023
Line 1:		Line 1:

	==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==		==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==
-	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]]' scene=''>	+	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]], [[Resolution\|resolution]] 1.83Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7jxq]] 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=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>
-	</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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></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]] 1.83Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=VNS:(2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide'>VNS</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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>
	</table>		</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 ==
		+	Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.
		+
		+	An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.,To C, Beyett TS, Jang J, Feng WW, Bahcall M, Haikala HM, Shin BH, Heppner DE, Rana JK, Leeper BA, Soroko KM, Poitras MJ, Gokhale PC, Kobayashi Y, Wahid K, Kurppa KJ, Gero TW, Cameron MD, Ogino A, Mushajiang M, Xu C, Zhang Y, Scott DA, Eck MJ, Gray NS, Janne PA Nat Cancer. 2022 Apr 14. pii: 10.1038/s43018-022-00351-8. doi:, 10.1038/s43018-022-00351-8. PMID:35422503<ref>PMID:35422503</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7jxq" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Beyett TS]]		[[Category: Beyett TS]]
	[[Category: Eck MJ]]		[[Category: Eck MJ]]

OCA at 14:44, 31 August 2022

OCA — Wed, 31 Aug 2022 14:44:05 GMT

←Older revision		Revision as of 14:44, 31 August 2022
Line 1:		Line 1:

	==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==		==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==
-	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]]~~, [[Resolution\|resolution]] 1.83Å~~' scene=''>	+	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7jxq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human].~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=VNS:(2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide'>VNS</scene></td></tr>	+	</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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>	+
	</table>		</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 ==
-	Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.
-
-	An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.,To C, Beyett TS, Jang J, Feng WW, Bahcall M, Haikala HM, Shin BH, Heppner DE, Rana JK, Leeper BA, Soroko KM, Poitras MJ, Gokhale PC, Kobayashi Y, Wahid K, Kurppa KJ, Gero TW, Cameron MD, Ogino A, Mushajiang M, Xu C, Zhang Y, Scott DA, Eck MJ, Gray NS, Janne PA Nat Cancer. 2022 Apr 14. pii: 10.1038/s43018-022-00351-8. doi:, 10.1038/s43018-022-00351-8. PMID:35422503<ref>PMID:35422503</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 7jxq" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Beyett TS]]
-	[[Category: Beyett~~, T S~~]]	+	[[Category: Eck MJ]]
-	[[Category: Eck~~, M J]]~~	+
-	~~[[Category: Egfr]]~~	+
-	~~[[Category: Erbb1]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 11:49, 27 April 2022

OCA — Wed, 27 Apr 2022 11:49:27 GMT

←Older revision		Revision as of 11:49, 27 April 2022
Line 1:		Line 1:

	==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==		==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==
-	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]]' scene=''>	+	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]], [[Resolution\|resolution]] 1.83Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7jxq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>
-	</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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=VNS:(2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide'>VNS</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>
	</table>		</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 ==
		+	Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.
		+
		+	An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.,To C, Beyett TS, Jang J, Feng WW, Bahcall M, Haikala HM, Shin BH, Heppner DE, Rana JK, Leeper BA, Soroko KM, Poitras MJ, Gokhale PC, Kobayashi Y, Wahid K, Kurppa KJ, Gero TW, Cameron MD, Ogino A, Mushajiang M, Xu C, Zhang Y, Scott DA, Eck MJ, Gray NS, Janne PA Nat Cancer. 2022 Apr 14. pii: 10.1038/s43018-022-00351-8. doi:, 10.1038/s43018-022-00351-8. PMID:35422503<ref>PMID:35422503</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7jxq" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Beyett TS]]	+	[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Eck MJ]]	+	[[Category: Beyett, T S]]
		+	[[Category: Eck, M J]]
		+	[[Category: Egfr]]
		+	[[Category: Erbb1]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 08:57, 8 September 2021

OCA — Wed, 08 Sep 2021 08:57:46 GMT

←Older revision		Revision as of 08:57, 8 September 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7jxq ~~is ON HOLD until Paper Publication~~	+	==EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063==
-		+	<StructureSection load='7jxq' size='340' side='right'caption='[[7jxq]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JXQ FirstGlance]. <br>
-	~~Description~~:	+	</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=7jxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jxq OCA], [https://pdbe.org/7jxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jxq RCSB], [https://www.ebi.ac.uk/pdbsum/7jxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jxq ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Beyett TS]]
		+	[[Category: Eck MJ]]

OCA at 06:48, 21 October 2020

OCA — Wed, 21 Oct 2020 06:48:32 GMT

←Older revision		Revision as of 06:48, 21 October 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7jxq is ON HOLD	+	The entry 7jxq is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7jxq" [edit=sysop:move=sysop]

OCA — Wed, 02 Sep 2020 05:28:29 GMT

Protected "7jxq" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:28, 2 September 2020

OCA: New page: '''Unreleased structure''' The entry 7jxq is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 02 Sep 2020 05:28:28 GMT

New page: '''Unreleased structure''' The entry 7jxq is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7jxq is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]