5kit

<StructureSection load='5kit' size='340' side='right' caption='[[5kit]], [[Resolution|resolution]] 1.60&Aring;' scene=''>

<table><tr><td colspan='2'>[[5kit]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KIT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KIT FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6TA:~{TERT}-BUTYL+(2~{S})-2-[(1,3-DIHYDROPYRROLO[3,4-C]PYRIDIN-2-YLCARBONYLAMINO)METHYL]-6-AZASPIRO[2.5]OCTANE-6-CARBOXYLATE'>6TA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>

<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>

<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=5kit FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kit OCA], [http://pdbe.org/5kit PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kit RCSB], [http://www.ebi.ac.uk/pdbsum/5kit PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kit ProSAT]</span></td></tr>

[[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).

NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.

 

<div class="pdbe-citations 5kit" style="background-color:#fffaf0;"></div>

== References ==

[[Category: Nicotinamide phosphoribosyltransferase]]

[[Category: Li, D]]

[[Category: Wang, W]]

[[Category: Transferase]]

[[Category: Transferase-transferase inhibitor complex]]