5can - Revision history

OCA at 12:19, 6 March 2024

OCA — Wed, 06 Mar 2024 12:19:38 GMT

←Older revision		Revision as of 12:19, 6 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5can]] 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=5CAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CAN FirstGlance]. <br>		<table><tr><td colspan='2'>[[5can]] 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=5CAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CAN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [https://pdbe.org/5can PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [https://www.ebi.ac.uk/pdbsum/5can PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5can 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=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [https://pdbe.org/5can PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [https://www.ebi.ac.uk/pdbsum/5can PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5can ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== 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>		[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 ==
-	Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.
-
-	Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.,Heald R, Bowman KK, Bryan MC, Burdick D, Chan B, Chan E, Chen Y, Clausen S, Dominguez-Fernandez B, Eigenbrot C, Elliott R, Hanan EJ, Jackson P, Knight J, La H, Lainchbury M, Malek S, Mann S, Merchant M, Mortara K, Purkey H, Schaefer G, Schmidt S, Seward E, Sideris S, Shao L, Wang S, Yeap K, Yen I, Yu C, Heffron TP J Med Chem. 2015 Nov 25;58(22):8877-95. doi: 10.1021/acs.jmedchem.5b01412. Epub, 2015 Nov 12. PMID:26455919<ref>PMID:26455919</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5can" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 06:26, 7 June 2023

OCA — Wed, 07 Jun 2023 06:26:27 GMT

←Older revision		Revision as of 06:26, 7 June 2023
Line 3:		Line 3:
	<StructureSection load='5can' size='340' side='right'caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='5can' size='340' side='right'caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5can]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CAN OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5CAN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5can]] 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=5CAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CAN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://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=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [https://pdbe.org/5can PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [https://www.ebi.ac.uk/pdbsum/5can PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5can ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [~~http~~://pdbe.org/5can PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5can PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5can ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[~~http~~://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.	+	[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 ==		== Function ==
-	[~~[http~~://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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Eigenbrot C]]
-	[[Category: Eigenbrot, C]]	+	[[Category: Yu C]]
-	[[Category: Yu, C]]	+
-	~~[[Category: Protein kinase inhibitor]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 11:30, 27 March 2020

OCA — Fri, 27 Mar 2020 11:30:00 GMT

←Older revision		Revision as of 11:30, 27 March 2020
Line 1:		Line 1:

	==EGFR kinase domain mutant "TMLR" with compound 27==		==EGFR kinase domain mutant "TMLR" with compound 27==
-	<StructureSection load='5can' size='340' side='right' caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>	+	<StructureSection load='5can' size='340' side='right'caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5can]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CAN FirstGlance]. <br>		<table><tr><td colspan='2'>[[5can]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CAN FirstGlance]. <br>
Line 23:		Line 23:

	==See Also==		==See Also==
-	*[[Epidermal ~~Growth Factor Receptor~~\|Epidermal ~~Growth Factor Receptor~~]]	+	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Eigenbrot, C]]		[[Category: Eigenbrot, C]]

OCA at 16:54, 18 August 2017

OCA — Fri, 18 Aug 2017 16:54:48 GMT

←Older revision		Revision as of 16:54, 18 August 2017
Line 1:		Line 1:
		+
	==EGFR kinase domain mutant "TMLR" with compound 27==		==EGFR kinase domain mutant "TMLR" with compound 27==
	<StructureSection load='5can' size='340' side='right' caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='5can' size='340' side='right' caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [http://pdbe.org/5can PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [http://www.ebi.ac.uk/pdbsum/5can PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [http://pdbe.org/5can PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [http://www.ebi.ac.uk/pdbsum/5can PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5can ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 5can" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5can" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Epidermal Growth Factor Receptor\|Epidermal Growth Factor Receptor]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 19:38, 30 November 2015

OCA — Mon, 30 Nov 2015 19:38:32 GMT

←Older revision		Revision as of 19:38, 30 November 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==EGFR kinase domain mutant "TMLR" with compound 27==
		+	<StructureSection load='5can' size='340' side='right' caption='[[5can]], [[Resolution\|resolution]] 2.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5can]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CAN FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZB:(3R)-3-METHYL-1-(4-{[2-METHYL-1-(PROPAN-2-YL)-1H-IMIDAZO[4,5-C]PYRIDIN-6-YL]AMINO}PYRIMIDIN-2-YL)PYRROLIDINE-3-CARBOXAMIDE'>4ZB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5can OCA], [http://pdbe.org/5can PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5can RCSB], [http://www.ebi.ac.uk/pdbsum/5can PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[http://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 ==
		+	[[http://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 ==
		+	Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

-	~~The entry 5can is ON HOLD until Paper Publication~~	+	Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.,Heald R, Bowman KK, Bryan MC, Burdick D, Chan B, Chan E, Chen Y, Clausen S, Dominguez-Fernandez B, Eigenbrot C, Elliott R, Hanan EJ, Jackson P, Knight J, La H, Lainchbury M, Malek S, Mann S, Merchant M, Mortara K, Purkey H, Schaefer G, Schmidt S, Seward E, Sideris S, Shao L, Wang S, Yeap K, Yen I, Yu C, Heffron TP J Med Chem. 2015 Nov 25;58(22):8877-95. doi: 10.1021/acs.jmedchem.5b01412. Epub, 2015 Nov 12. PMID:26455919<ref>PMID:26455919</ref>

-	~~Authors: Eigenbrot~~, C.~~, Yu, C~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~:	+	<div class="pdbe-citations 5can" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Eigenbrot, C]]		[[Category: Eigenbrot, C]]
	[[Category: Yu, C]]		[[Category: Yu, C]]
		+	[[Category: Protein kinase inhibitor]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 12:19, 15 July 2015

OCA — Wed, 15 Jul 2015 12:19:24 GMT

←Older revision		Revision as of 12:19, 15 July 2015
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-	The entry 5can is ON HOLD	+	The entry 5can is ON HOLD until Paper Publication

	Authors: Eigenbrot, C., Yu, C.		Authors: Eigenbrot, C., Yu, C.

OCA: Protected "5can" [edit=sysop:move=sysop]

OCA — Wed, 08 Jul 2015 13:54:41 GMT

Protected "5can" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:54, 8 July 2015

OCA: New page: '''Unreleased structure''' The entry 5can is ON HOLD Authors: Eigenbrot, C., Yu, C. Description: Category: Unreleased Structures Category: Eigenbrot, C Category: Yu, C

OCA — Wed, 08 Jul 2015 13:54:40 GMT

New page: '''Unreleased structure''' The entry 5can is ON HOLD Authors: Eigenbrot, C., Yu, C. Description: Category: Unreleased Structures Category: Eigenbrot, C Category: Yu, C

New page

'''Unreleased structure'''

The entry 5can is ON HOLD

Authors: Eigenbrot, C., Yu, C.

Description:
[[Category: Unreleased Structures]]
[[Category: Eigenbrot, C]]
[[Category: Yu, C]]