RRC ID 44837
著者 Takeuchi M, Niimi T, Masumoto M, Orita M, Yokota H, Yamamoto T.
タイトル Discovery of a novel nicotinamide phosphoribosyl transferase (NAMPT) inhibitor via in silico screening.
ジャーナル Biol Pharm Bull
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.
巻・号 37(1)
ページ 31-6
公開日 2014-1-1
DOI 10.1248/bpb.b13-00495
PII DN/JST.JSTAGE/bpb/b13-00495
PMID 24389478
MeSH Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Apoptosis Computer Simulation* Drug Discovery / methods* Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Enzyme Inhibitors / therapeutic use Humans Inhibitory Concentration 50 K562 Cells Leukemia / drug therapy Leukemia / enzymology* Mice NAD / biosynthesis* Niacinamide / metabolism Nicotinamide Mononucleotide / biosynthesis Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
IF 1.863
引用数 6
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 K562