4uwk

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==Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6- one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors==
==Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6- one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors==
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<StructureSection load='4uwk' size='340' side='right' caption='[[4uwk]], [[Resolution|resolution]] 2.83&Aring;' scene=''>
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<StructureSection load='4uwk' size='340' side='right'caption='[[4uwk]], [[Resolution|resolution]] 2.83&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4uwk]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UWK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UWK FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4uwk]] 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=4UWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UWK FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UJB:(2S)-1-[(5-CHLORO-2-THIENYL)METHYL]-8-[(3R,5R)-3,5-DIMETHYLMORPHOLIN-4-YL]-2-(TRIFLUOROMETHYL)-3,4-DIHYDRO-2H-PYRIMIDO[1,2-A]PYRIMIDIN-6-ONE'>UJB</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.83&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uwh|4uwh]], [[4uwl|4uwl]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UJB:(2S)-1-[(5-CHLORO-2-THIENYL)METHYL]-8-[(3R,5R)-3,5-DIMETHYLMORPHOLIN-4-YL]-2-(TRIFLUOROMETHYL)-3,4-DIHYDRO-2H-PYRIMIDO[1,2-A]PYRIMIDIN-6-ONE'>UJB</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase Phosphatidylinositol 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.137 2.7.1.137] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uwk OCA], [https://pdbe.org/4uwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uwk RCSB], [https://www.ebi.ac.uk/pdbsum/4uwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uwk ProSAT]</span></td></tr>
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<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=4uwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uwk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4uwk RCSB], [http://www.ebi.ac.uk/pdbsum/4uwk PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>
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Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimido-pyrimidinone derivatives. Starting with hit compound 1, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrated how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
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Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxo-butyl)-2-(trifluoromethyl) -3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors.,Pasquier B, El-Ahmad Y, Filoche-Romme B, Dureuil-Sizaire C, Fassy F, Abecassis PY, Mathieu M, Bertrand T, Benard T, Barriere C, El Batti S, Letallec JP, Sonnefraud V, Brollo M, Delbarre L, Loyau V, Pilorge F, Bertin L, Richepin P, Arigon J, Labrosse JR, Clement J, Durand F, Combet R, Perraut P, Leroy V, Gay F, Lefrancois D, Bretin F, Marquette JP, Michot N, Caron A, Castell C, Schio L, McCort G, Goulaouic H, Garcia-Echeverria C, Ronan BP J Med Chem. 2014 Nov 17. PMID:25402320<ref>PMID:25402320</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Phosphatidylinositol 3-kinase]]
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[[Category: Homo sapiens]]
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[[Category: Abecassis, P Y]]
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[[Category: Large Structures]]
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[[Category: Arigon, J]]
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[[Category: Abecassis PY]]
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[[Category: Barriere, C]]
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[[Category: Arigon J]]
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[[Category: Benard, T]]
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[[Category: Barriere C]]
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[[Category: Bertin, L]]
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[[Category: Benard T]]
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[[Category: Bertrand, T]]
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[[Category: Bertin L]]
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[[Category: Bretin, F]]
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[[Category: Bertrand T]]
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[[Category: Brollo, M]]
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[[Category: Bretin F]]
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[[Category: Caron, A]]
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[[Category: Brollo M]]
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[[Category: Castell, C]]
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[[Category: Caron A]]
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[[Category: Clement, J]]
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[[Category: Castell C]]
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[[Category: Combet, R]]
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[[Category: Clement J]]
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[[Category: Delbarre, L]]
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[[Category: Combet R]]
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[[Category: Durand, F]]
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[[Category: Delbarre L]]
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[[Category: Dureuil, C]]
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[[Category: Durand F]]
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[[Category: El-Ahmad, Y]]
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[[Category: Dureuil C]]
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[[Category: ElBatti, S]]
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[[Category: El-Ahmad Y]]
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[[Category: Fassy, F]]
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[[Category: ElBatti S]]
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[[Category: Filoche-Romme, B]]
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[[Category: Fassy F]]
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[[Category: Garcia-Echeverria, C]]
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[[Category: Filoche-Romme B]]
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[[Category: Gay, F]]
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[[Category: Garcia-Echeverria C]]
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[[Category: Goulaouic, H]]
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[[Category: Gay F]]
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[[Category: Labrosse, J R]]
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[[Category: Goulaouic H]]
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[[Category: Lefrancois, D]]
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[[Category: Labrosse JR]]
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[[Category: Leroy, V]]
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[[Category: Lefrancois D]]
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[[Category: Letallec, J P]]
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[[Category: Leroy V]]
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[[Category: Loyau, V]]
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[[Category: Letallec JP]]
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[[Category: Marquette, J P]]
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[[Category: Loyau V]]
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[[Category: Mathieu, M]]
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[[Category: Marquette JP]]
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[[Category: McCort, G]]
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[[Category: Mathieu M]]
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[[Category: Michot, N]]
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[[Category: McCort G]]
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[[Category: Pasquier, B]]
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[[Category: Michot N]]
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[[Category: Perraut, P]]
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[[Category: Pasquier B]]
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[[Category: Pilorge, F]]
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[[Category: Perraut P]]
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[[Category: Richepin, P]]
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[[Category: Pilorge F]]
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[[Category: Ronan, B]]
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[[Category: Richepin P]]
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[[Category: Schio, L]]
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[[Category: Ronan B]]
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[[Category: Sonnefraud, V]]
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[[Category: Schio L]]
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[[Category: Autophagy inhibitor]]
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[[Category: Sonnefraud V]]
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[[Category: Lipid kinase]]
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[[Category: Transferase]]
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Current revision

Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6- one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

PDB ID 4uwk

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