4lts

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{{STRUCTURE_4lts| PDB=4lts | SCENE= }}
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==Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors==
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===Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors===
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<StructureSection load='4lts' size='340' side='right' caption='[[4lts]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24279990}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4lts]] is a 2 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=4LTS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LTS FirstGlance]. <br>
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==Function==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LTS:2-CYANO-1-PYRIDIN-4-YL-3-(4-{[3-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}BENZYL)GUANIDINE'>LTS</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lww|4lww]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAMPT, PBEF, PBEF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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/Nicotinamide_phosphoribosyltransferase Nicotinamide phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.12 2.4.2.12] </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=4lts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lts OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lts RCSB], [http://www.ebi.ac.uk/pdbsum/4lts PDBsum]</span></td></tr>
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</table>
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== Function ==
[[http://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN]] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity).
[[http://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN]] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.
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Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.,Zheng X, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Wang Y, Yuen PW, Bair KW Bioorg Med Chem Lett. 2013 Nov 14. pii: S0960-894X(13)01285-7. doi:, 10.1016/j.bmcl.2013.11.006. PMID:24279990<ref>PMID:24279990</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4lts]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LTS OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:024279990</ref><references group="xtra"/><references/>
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*[[Phosphoribosyltransferase|Phosphoribosyltransferase]]
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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: Nicotinamide phosphoribosyltransferase]]
[[Category: Nicotinamide phosphoribosyltransferase]]
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[[Category: Bair, K W.]]
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[[Category: Bair, K W]]
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[[Category: Baumeister, T.]]
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[[Category: Baumeister, T]]
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[[Category: Buckmelter, A J.]]
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[[Category: Buckmelter, A J]]
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[[Category: Caligiuri, M.]]
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[[Category: Caligiuri, M]]
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[[Category: Clodfelter, K H.]]
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[[Category: Clodfelter, K H]]
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[[Category: Dragovich, P S.]]
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[[Category: Dragovich, P S]]
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[[Category: Han, B.]]
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[[Category: Han, B]]
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[[Category: Ho, Y.]]
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[[Category: Ho, Y]]
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[[Category: Kley, N.]]
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[[Category: Kley, N]]
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[[Category: Lin, J.]]
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[[Category: Lin, J]]
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[[Category: Oh, A.]]
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[[Category: Oh, A]]
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[[Category: Reynoids, D J.]]
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[[Category: Reynoids, D J]]
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[[Category: Sharma, G.]]
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[[Category: Sharma, G]]
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[[Category: Smith, C C.]]
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[[Category: Smith, C C]]
[[Category: Wang, L]]
[[Category: Wang, L]]
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[[Category: Wang, W.]]
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[[Category: Wang, W]]
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[[Category: Wang, Z.]]
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[[Category: Wang, Z]]
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[[Category: Yuen, P.]]
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[[Category: Yuen, P]]
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[[Category: Zak, M.]]
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[[Category: Zak, M]]
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[[Category: Zheng, X.]]
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[[Category: Zheng, X]]
[[Category: Transferase]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 08:34, 25 December 2014

Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

4lts, resolution 1.69Å

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