4lts
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| - | {{STRUCTURE_4lts| PDB=4lts | SCENE= }} | ||
| - | ===Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors=== | ||
| - | {{ABSTRACT_PUBMED_24279990}} | ||
| - | == | + | ==Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors== |
| - | [[http://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN | + | <StructureSection load='4lts' size='340' side='right'caption='[[4lts]], [[Resolution|resolution]] 1.69Å' scene=''> |
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4lts]] is a 2 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=4LTS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LTS FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.692Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lts OCA], [https://pdbe.org/4lts PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lts RCSB], [https://www.ebi.ac.uk/pdbsum/4lts PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lts ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://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). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| - | + | 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> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | < | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 4lts" style="background-color:#fffaf0;"></div> |
| - | [[Category: Bair | + | |
| - | [[Category: Baumeister | + | ==See Also== |
| - | [[Category: Buckmelter | + | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] |
| - | [[Category: Caligiuri | + | == References == |
| - | [[Category: Clodfelter | + | <references/> |
| - | [[Category: Dragovich | + | __TOC__ |
| - | [[Category: Han | + | </StructureSection> |
| - | [[Category: Ho | + | [[Category: Homo sapiens]] |
| - | [[Category: Kley | + | [[Category: Large Structures]] |
| - | [[Category: Lin | + | [[Category: Bair KW]] |
| - | [[Category: Oh | + | [[Category: Baumeister T]] |
| - | [[Category: Reynoids | + | [[Category: Buckmelter AJ]] |
| - | [[Category: Sharma | + | [[Category: Caligiuri M]] |
| - | [[Category: Smith | + | [[Category: Clodfelter KH]] |
| - | [[Category: Wang | + | [[Category: Dragovich PS]] |
| - | [[Category: Wang | + | [[Category: Han B]] |
| - | [[Category: Wang | + | [[Category: Ho Y]] |
| - | [[Category: Yuen | + | [[Category: Kley N]] |
| - | [[Category: Zak | + | [[Category: Lin J]] |
| - | [[Category: Zheng | + | [[Category: Oh A]] |
| - | + | [[Category: Reynoids DJ]] | |
| - | + | [[Category: Sharma G]] | |
| + | [[Category: Smith CC]] | ||
| + | [[Category: Wang L]] | ||
| + | [[Category: Wang W]] | ||
| + | [[Category: Wang Z]] | ||
| + | [[Category: Yuen P]] | ||
| + | [[Category: Zak M]] | ||
| + | [[Category: Zheng X]] | ||
Current revision
Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
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Categories: Homo sapiens | Large Structures | Bair KW | Baumeister T | Buckmelter AJ | Caligiuri M | Clodfelter KH | Dragovich PS | Han B | Ho Y | Kley N | Lin J | Oh A | Reynoids DJ | Sharma G | Smith CC | Wang L | Wang W | Wang Z | Yuen P | Zak M | Zheng X
