title: Discovery of a novel nicotinamide phosphoribosyl transferase (NAMPT) inhibitor via in silico screening.
abstract: Nicotinamide phosphoribosyl transferase (NAMPT) is a key enzyme in the salvage pathway of mammalian nicotinamide adenine dinucleotide (NAD) biosynthesis, catalyzing the synthesis of nicotinamide mononucleotide from nicotinamide (Nam). The diverse functions of NAD suggest that NAMPT inhibitors are potential drug candidates as anticancer agents, immunomodulators, or other agents. However, difficulty in conducting high-throughput NAMPT assay with good sensitivity has hampered the discovery of novel anti-NAMPT drugs with improved profiles. We combined an in silico screening strategy with a radioisotope (RI)-based enzyme assay and rationally identified promising NAMPT inhibitors with novel structures. AS1604498 was the most potent inhibitor, with an IC50 of 44 nM, and inhibited THP-1 and K562 cell line growth with the IC50 of 198 nM and 673 nM, respectively. The mode of action was found to reduce intracellular NAD following apoptosis, suggesting that these compounds inhibit NAMPT in cell-based assay. This strategy can be used to discover new drug candidates with targets which are difficult to assess through high-throughput screening. Our hit compounds may be used as seed compounds for developing new therapeutics with NAMPT.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc.
authors.forename: Mikio
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Mari
authors.initials: M
authors.lastname: Masumoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yokota
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D009243:NAD / Q000096:biosynthesis*; D009536:Niacinamide / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000096:biosynthesis; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009243:NAD; D009537:Nicotinamide Mononucleotide; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase