4lvb

Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

spinqualitylabelsall models 4lvb, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4lvb is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 20N, EDO, PO4 Related: 4lv9, 4lva, 4lvd, 4lvf, 4lvg, 4m6p, 4m6q Gene: NAMPT, PBEF, PBEF1 (HUMAN) Activity: Nicotinamide phosphoribosyltransferase, with EC number 2.4.2.12 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, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained. Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Zheng X, Bair KW, Bauer P, Baumeister T, Bowman KK, Buckmelter AJ, Caligiuri M, Clodfelter KH, Feng Y, Han B, Ho YC, Kley N, Li H, Liang X, Liederer BM, Lin J, Ly J, O'Brien T, Oeh J, Oh A, Reynolds DJ, Sampath D, Sharma G, Skelton N, Smith CC, Tremayne J, Wang L, Wang W, Wang Z, Wu H, Wu J, Xiao Y, Yang G, Yuen PW, Zak M, Dragovich PS Bioorg Med Chem Lett. 2013 Oct 15;23(20):5488-97. doi:, 10.1016/j.bmcl.2013.08.074. Epub 2013 Aug 22. PMID:24021463 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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