4n9d
Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
Structural highlights
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 PubMedThe fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Dragovich PS, Zhao G, Baumeister T, Bravo B, Giannetti AM, Ho YC, Hua R, Li G, Liang X, Ma X, O'Brien T, Oh A, Skelton NJ, Wang C, Wang W, Wang Y, Xiao Y, Yuen PW, Zak M, Zhao Q, Zheng X Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062., Epub 2013 Dec 21. PMID:24433859[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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