4jnm | pdb_00004jnm

Discovery of Potent and Efficacious Urea-containing Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors with Reduced CYP2C9 Inhibition Properties

spinqualitylabelsall models 4jnm, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jnm is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1LJ, EDO, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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). Publication Abstract from PubMed Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3nM; A2780 antiproliferative IC50=70nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described. Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.,Gunzner-Toste J, Zhao G, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Fu B, Han B, Ho YC, Kley N, Liang X, Liederer BM, Lin J, Mukadam S, O'Brien T, Oh A, Reynolds DJ, Sharma G, Skelton N, Smith CC, Sodhi J, Wang W, Wang Z, Xiao Y, Yuen PW, Zak M, Zhang L, Zheng X, Bair KW, Dragovich PS Bioorg Med Chem Lett. 2013 Jun 15;23(12):3531-8. doi: 10.1016/j.bmcl.2013.04.040., Epub 2013 Apr 25. PMID:23668988 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoribosyltransferase 3D structures

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