3ml8 - Revision history

OCA at 10:25, 21 February 2024

OCA — Wed, 21 Feb 2024 10:25:44 GMT

←Older revision		Revision as of 10:25, 21 February 2024
Line 1:		Line 1:

	==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==		==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==
-	<StructureSection load='3ml8' size='340' side='right' caption='[[3ml8]], [[Resolution\|resolution]] 2.70Å' scene=''>	+	<StructureSection load='3ml8' size='340' side='right'caption='[[3ml8]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3ml8]] 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=3ML8 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3ML8 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3ml8]] 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=3ML8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ML8 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=ML8:8-CYCLOPENTYL-6-[3-(HYDROXYMETHYL)PHENYL]-4-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>ML8</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]] 2.7Å</td></tr>
-	~~<tr~~ id~~='related'><td class~~="~~sblockLbl~~">~~<b>~~[[~~Related_structure~~\|~~Related:]]</b></td><td class="sblockDat">[[3ml9\|3ml9~~]]</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ML8:8-CYCLOPENTYL-6-[3-(HYDROXYMETHYL)PHENYL]-4-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>ML8</scene></td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</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=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [https://pdbe.org/3ml8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ml8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ml8 ProSAT]</span></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Phosphatidylinositol~~-4,5-~~bisphosphate_3~~-~~kinase Phosphatidylinositol~~-4,~~5-bisphosphate~~ 3-~~kinase~~]~~, with EC number [http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=2.~~7~~.1.153 2.7.1.153]~~ </~~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=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [~~http~~://pdbe.org/3ml8 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3ml8 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3ml8 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>	+	[https://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ml/3ml8_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ml/3ml8_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 22:		Line 20:
	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ml8 ConSurf].		</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ml8 ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

-	Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.,Cheng H, Li C, Bailey S, Baxi SM, Goulet L, Guo L, Hoffman J, Jiang Y, Johnson TO, Johnson TW, Knighton DR, Li J, Liu KK, Liu Z, Marx MA, Walls M, Wells PA, Yin MJ, Zhu J, Zientek M ACS Med Chem Lett. 2012 Nov 7;4(1):91-7. doi: 10.1021/ml300309h. eCollection 2013, Jan 10. PMID:24900568<ref>PMID:24900568</ref>	+	==See Also==
-		+	*[[Phosphoinositide 3-kinase 3D structures\|Phosphoinositide 3-kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe~~-~~citations 3ml8" style="background~~-~~color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Phosphatidylinositol-4,5-bisphosphate 3-kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Knighton~~, D R]]~~	+	[[Category: Knighton DR]]
-	~~[[Category: Inhibition]]~~	+
-	~~[[Category: Phosphoinositide kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:14, 8 November 2017

OCA — Wed, 08 Nov 2017 08:14:01 GMT

←Older revision		Revision as of 08:14, 8 November 2017
Line 31:		Line 31:
	</div>		</div>
	<div class="pdbe-citations 3ml8" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3ml8" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:18, 4 August 2016

OCA — Thu, 04 Aug 2016 14:18:40 GMT

←Older revision		Revision as of 14:18, 4 August 2016
Line 1:		Line 1:
		+
	==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==		==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==
	<StructureSection load='3ml8' size='340' side='right' caption='[[3ml8]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='3ml8' size='340' side='right' caption='[[3ml8]], [[Resolution\|resolution]] 2.70Å' scene=''>
Line 7:		Line 8:
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([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/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </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=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [http://www.ebi.ac.uk/pdbsum/3ml8 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=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [http://pdbe.org/3ml8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [http://www.ebi.ac.uk/pdbsum/3ml8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ml8 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 20:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ml8 ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 29:		Line 30:
	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 3ml8" style="background-color:#fffaf0;"></div>

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

OCA at 10:04, 25 December 2014

OCA — Thu, 25 Dec 2014 10:04:58 GMT

←Older revision		Revision as of 10:04, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3ml8]] 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=3ML8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ML8 FirstGlance]. <br>		<table><tr><td colspan='2'>[[3ml8]] 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=3ML8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ML8 FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ML8:8-CYCLOPENTYL-6-[3-(HYDROXYMETHYL)PHENYL]-4-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>ML8</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ML8:8-CYCLOPENTYL-6-[3-(HYDROXYMETHYL)PHENYL]-4-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>ML8</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ml9\|3ml9]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ml9\|3ml9]]</td></tr>
-	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [http://www.ebi.ac.uk/pdbsum/3ml8 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=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [http://www.ebi.ac.uk/pdbsum/3ml8 PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 36:		Line 38:
	[[Category: Human]]		[[Category: Human]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
-	[[Category: Knighton, D R.]]	+	[[Category: Knighton, D R]]
	[[Category: Inhibition]]		[[Category: Inhibition]]
	[[Category: Phosphoinositide kinase]]		[[Category: Phosphoinositide kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:16, 9 July 2014

OCA — Wed, 09 Jul 2014 06:16:49 GMT

←Older revision		Revision as of 06:16, 9 July 2014
Line 1:		Line 1:
-	[[~~Image:~~3ml8.~~png~~\|~~left~~\|200px]]	+	==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==
		+	<StructureSection load='3ml8' size='340' side='right' caption='[[3ml8]], [[Resolution\|resolution]] 2.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3ml8]] 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=3ML8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ML8 FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ML8:8-CYCLOPENTYL-6-[3-(HYDROXYMETHYL)PHENYL]-4-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>ML8</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ml9\|3ml9]]</td></tr>
		+	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ml8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ml8 RCSB], [http://www.ebi.ac.uk/pdbsum/3ml8 PDBsum]</span></td></tr>
		+	<table>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ml/3ml8_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

-	~~{{STRUCTURE_3ml8\| PDB=3ml8 \| SCENE= }}~~	+	Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.,Cheng H, Li C, Bailey S, Baxi SM, Goulet L, Guo L, Hoffman J, Jiang Y, Johnson TO, Johnson TW, Knighton DR, Li J, Liu KK, Liu Z, Marx MA, Walls M, Wells PA, Yin MJ, Zhu J, Zientek M ACS Med Chem Lett. 2012 Nov 7;4(1):91-7. doi: 10.1021/ml300309h. eCollection 2013, Jan 10. PMID:24900568<ref>PMID:24900568</ref>

-	~~===Discovery~~ of the ~~Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-		+
-	~~==About this Structure==~~	+
-	~~[[3ml8]] is a 1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].~~	+

	==See Also==		==See Also==
	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]		*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
-	[[Category: ~~Homo sapiens~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
	[[Category: Knighton, D R.]]		[[Category: Knighton, D R.]]

OCA at 15:25, 20 October 2012

OCA — Sat, 20 Oct 2012 15:25:21 GMT

←Older revision		Revision as of 15:25, 20 October 2012
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	==About this Structure==		==About this Structure==
-	[[3ml8]] is a 1 chain structure ~~of [[Phosphoinositide 3-Kinases]]~~ with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].	+	[[3ml8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].

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

OCA: Protected "3ml8" [edit=sysop:move=sysop]

OCA — Thu, 26 Jul 2012 18:20:04 GMT

Protected "3ml8" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:20, 26 July 2012

OCA at 18:20, 26 July 2012

OCA — Thu, 26 Jul 2012 18:20:02 GMT

←Older revision		Revision as of 18:20, 26 July 2012
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-	~~{{Seed}}~~	+	[[Image:3ml8.png\|left\|200px]]
-	[[Image:3ml8.~~jpg~~\|left\|200px]]	+

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3ml8", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3ml8\| PDB=3ml8 \| SCENE= }}		{{STRUCTURE_3ml8\| PDB=3ml8 \| SCENE= }}

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	==About this Structure==		==About this Structure==
-	~~3ML8~~ is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].	+	[[3ml8]] is a 1 chain structure of [[Phosphoinositide 3-Kinases]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].
		+
		+	==See Also==
		+	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
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	[[Category: Phosphoinositide kinase]]		[[Category: Phosphoinositide kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]
-	[[Category: Transferase-transferase ~~inhibiator~~ complex]]	+	[[Category: Transferase-transferase inhibitor complex]]
-		+
-	~~''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 2 08:39:49 2010''~~	+

OCA at 04:35, 2 June 2010

OCA — Wed, 02 Jun 2010 04:35:22 GMT

←Older revision		Revision as of 04:35, 2 June 2010
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-	~~'''Unreleased structure'''~~	+	{{Seed}}
		+	[[Image:3ml8.jpg\|left\|200px]]

-	The ~~entry 3ml8~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3ml8", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3ml8\| PDB=3ml8 \| SCENE= }}

-	~~Authors: Knighton, D.R.~~	+	===Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design===

-	Description: Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed ~~May 26~~ 08:21:55 2010''	+	==About this Structure==
		+	3ML8 is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ML8 OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
		+	[[Category: Knighton, D R.]]
		+	[[Category: Inhibition]]
		+	[[Category: Phosphoinositide kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibiator complex]]
		+
		+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 2 08:39:49 2010''

OCA at 04:17, 26 May 2010

OCA — Wed, 26 May 2010 04:17:44 GMT

←Older revision		Revision as of 04:17, 26 May 2010
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3ml8 is ON HOLD	+	The entry 3ml8 is ON HOLD until Paper Publication

	Authors: Knighton, D.R.		Authors: Knighton, D.R.
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	Description: Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design		Description: Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May ~~5 11~~:40:05 2010''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May 26 08:21:55 2010''