6gqq - Revision history

OCA at 08:56, 3 October 2018

OCA — Wed, 03 Oct 2018 08:56:06 GMT

←Older revision		Revision as of 08:56, 3 October 2018
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	<StructureSection load='6gqq' size='340' side='right' caption='[[6gqq]], [[Resolution\|resolution]] 1.52Å' scene=''>		<StructureSection load='6gqq' size='340' side='right' caption='[[6gqq]], [[Resolution\|resolution]] 1.52Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6gqq]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GQQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GQQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6gqq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GQQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GQQ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F8B:~{N}-[4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-2-(4-propan-2-yl-1,2,3-triazol-1-yl)ethanamide'>F8B</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F8B:~{N}-[4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-2-(4-propan-2-yl-1,2,3-triazol-1-yl)ethanamide'>F8B</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KDR, FLK1, VEGFR2 ([http://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'>[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=6gqq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gqq OCA], [http://pdbe.org/6gqq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gqq RCSB], [http://www.ebi.ac.uk/pdbsum/6gqq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gqq 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=6gqq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gqq OCA], [http://pdbe.org/6gqq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gqq RCSB], [http://www.ebi.ac.uk/pdbsum/6gqq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gqq ProSAT]</span></td></tr>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Anjum, R]]		[[Category: Anjum, R]]

OCA at 19:58, 19 September 2018

OCA — Wed, 19 Sep 2018 19:58:04 GMT

←Older revision		Revision as of 19:58, 19 September 2018
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-	'''Unreleased structure'''

-	~~The entry~~ 6gqq is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of human KDR (VEGFR2) kinase domain in complex with AZD3229-analogue (compound 35)==
		+	<StructureSection load='6gqq' size='340' side='right' caption='[[6gqq]], [[Resolution\|resolution]] 1.52Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6gqq]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GQQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GQQ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F8B:~{N}-[4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-2-(4-propan-2-yl-1,2,3-triazol-1-yl)ethanamide'>F8B</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=6gqq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gqq OCA], [http://pdbe.org/6gqq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gqq RCSB], [http://www.ebi.ac.uk/pdbsum/6gqq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gqq ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:[http://omim.org/entry/602089 602089]]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma.<ref>PMID:11807987</ref> <ref>PMID:18931684</ref> Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.<ref>PMID:19668192</ref> <ref>PMID:1417831</ref> <ref>PMID:7929439</ref> <ref>PMID:9160888</ref> <ref>PMID:9837777</ref> <ref>PMID:9804796</ref> <ref>PMID:10600473</ref> <ref>PMID:10102632</ref> <ref>PMID:11387210</ref> <ref>PMID:12649282</ref> <ref>PMID:15026417</ref> <ref>PMID:15215251</ref> <ref>PMID:15962004</ref> <ref>PMID:16966330</ref> <ref>PMID:17303569</ref> <ref>PMID:19834490</ref> <ref>PMID:20179233</ref> <ref>PMID:20224550</ref> <ref>PMID:20705758</ref> <ref>PMID:10368301</ref> <ref>PMID:18529047</ref> <ref>PMID:20080685</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	While the treatment of Gastrointestinal Stromal Tumors (GIST) has been revolutionised by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multi-targeted agents. This effort focussed on identification and optimisation of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFR, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimised, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalised predominantly by the interaction of water molecules with the protein and ligand in the active site and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

-	~~Authors~~:	+	Discovery of N-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triaz ol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors.,Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy C, Hunt T, Jones R, Li X, Moleva O, Ogg D, Overman R, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith J, Stead D, Stokes S, Tucker M, Ye Y J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00938. PMID:30204441<ref>PMID:30204441</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 6gqq" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Anjum, R]]
		+	[[Category: Barry, E]]
		+	[[Category: Bhavsar, D]]
		+	[[Category: Brown, C]]
		+	[[Category: Campbell, A]]
		+	[[Category: Goldberg, K]]
		+	[[Category: Grondine, M]]
		+	[[Category: Guichard, S]]
		+	[[Category: Hardy, C J]]
		+	[[Category: Hunt, T]]
		+	[[Category: Jones, O]]
		+	[[Category: Kettle, J G]]
		+	[[Category: Li, X]]
		+	[[Category: Moleva, O]]
		+	[[Category: Ogg, D J]]
		+	[[Category: Overman, R C]]
		+	[[Category: Packer, M J]]
		+	[[Category: Pearson, S]]
		+	[[Category: Schimpl, M]]
		+	[[Category: Shao, W]]
		+	[[Category: Smith, A]]
		+	[[Category: Smith, J]]
		+	[[Category: Stead, D]]
		+	[[Category: Stokes, S]]
		+	[[Category: Tucker, M]]
		+	[[Category: Ye, Y]]
		+	[[Category: Gastrointestinal stromal tumour]]
		+	[[Category: Inhibitor]]
		+	[[Category: Oncology]]
		+	[[Category: Receptor tyrosine kinase]]
		+	[[Category: Signaling protein]]
		+	[[Category: Structure-based drug design]]

OCA at 04:20, 20 June 2018

OCA — Wed, 20 Jun 2018 04:20:20 GMT

←Older revision		Revision as of 04:20, 20 June 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6gqq is ON HOLD	+	The entry 6gqq is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6gqq" [edit=sysop:move=sysop]

OCA — Thu, 14 Jun 2018 06:02:35 GMT

Protected "6gqq" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:02, 14 June 2018

OCA: New page: '''Unreleased structure''' The entry 6gqq is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Thu, 14 Jun 2018 06:02:34 GMT

New page: '''Unreleased structure''' The entry 6gqq is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6gqq is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]