3ml8

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[[Image:3ml8.png|left|200px]]
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==Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design==
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<StructureSection load='3ml8' size='340' side='right' caption='[[3ml8]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<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>
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</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>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ml9|3ml9]]</td></tr>
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<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>
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<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>
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<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>
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<table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ml/3ml8_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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{{STRUCTURE_3ml8| PDB=3ml8 | SCENE= }}
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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>
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===Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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[[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].
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==See Also==
==See Also==
*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]]
*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]]
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[[Category: Homo sapiens]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
[[Category: Knighton, D R.]]
[[Category: Knighton, D R.]]

Revision as of 06:16, 9 July 2014

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

3ml8, resolution 2.70Å

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