Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor via in Silico Screening
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 po...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2014/01/01, Vol.37(1), pp.31-36 |
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| creator | Takeuchi, Mikio Niimi, Tatsuya Masumoto, Mari Orita, Masaya Yokota, Hiroyuki Yamamoto, Tomoko |
| description | 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 n M , and inhibited THP-1 and K562 cell line growth with the IC50 of 198 n M and 673 n M , 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. |
| doi_str_mv | 10.1248/bpb.b13-00495 |
| format | Article |
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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 n M , and inhibited THP-1 and K562 cell line growth with the IC50 of 198 n M and 673 n M , 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.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b13-00495</identifier><identifier>PMID: 24389478</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>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 ; FK866 ; Humans ; in silico screening ; Inhibitory Concentration 50 ; K562 Cells ; Leukemia - drug therapy ; Leukemia - enzymology ; Mice ; NAD - biosynthesis ; Niacinamide - metabolism ; nicotinamide adenine dinucleotide ; Nicotinamide Mononucleotide - biosynthesis ; nicotinamide phosphoribosyl transferase ; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors</subject><ispartof>Biological and Pharmaceutical Bulletin, 2014/01/01, Vol.37(1), pp.31-36</ispartof><rights>2014 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c658t-d5bc206a0015a9e145525b3fd6fb8ebcba2ab8f0f31cfc8d580349ff9e606ba23</citedby><cites>FETCH-LOGICAL-c658t-d5bc206a0015a9e145525b3fd6fb8ebcba2ab8f0f31cfc8d580349ff9e606ba23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24389478$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takeuchi, Mikio</creatorcontrib><creatorcontrib>Niimi, Tatsuya</creatorcontrib><creatorcontrib>Masumoto, Mari</creatorcontrib><creatorcontrib>Orita, Masaya</creatorcontrib><creatorcontrib>Yokota, Hiroyuki</creatorcontrib><creatorcontrib>Yamamoto, Tomoko</creatorcontrib><creatorcontrib>Chiba University</creatorcontrib><creatorcontrib>Astellas Pharma Inc</creatorcontrib><creatorcontrib>Drug Discovery Research</creatorcontrib><creatorcontrib>Department of Microbiology and Molecular Genetics</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences</creatorcontrib><title>Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor via in Silico Screening</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>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 n M , and inhibited THP-1 and K562 cell line growth with the IC50 of 198 n M and 673 n M , 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.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Computer Simulation</subject><subject>Drug Discovery - methods</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>FK866</subject><subject>Humans</subject><subject>in silico screening</subject><subject>Inhibitory Concentration 50</subject><subject>K562 Cells</subject><subject>Leukemia - drug therapy</subject><subject>Leukemia - enzymology</subject><subject>Mice</subject><subject>NAD - biosynthesis</subject><subject>Niacinamide - metabolism</subject><subject>nicotinamide adenine dinucleotide</subject><subject>Nicotinamide Mononucleotide - biosynthesis</subject><subject>nicotinamide phosphoribosyl transferase</subject><subject>Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFvEzEQhS0EoqFw5IoscSmHLWN7ves9VgFKpRIqNZwt27EbR44d7E2l_Hu8TQkSF89I8-nNGz-E3hO4JLQVn_VOX2rCGoB24C_QjLC2bzgl_CWawUBE0xEuztCbUjYA0ANlr9EZbZkY2l7MkPvii0mPNh9wcljhRe0DXniTRh_V1q8svlunslun7HUqh4CXWcXibFbF4ovF1Y-75Sd8E9de-zFl_OgV9hHf-1Al8L3J1kYfH96iV06FYt8913P069vX5fx7c_vz-mZ-dduYjouxWXFtKHQKgHA1WNJyTrlmbtU5Law2WlGlhQPHiHFGrLgA1g7ODbaDrg7ZObo46u5y-r23ZZTbep8NQUWb9kWSdoCeAIgJ_fgfukn7HKu7SvUCiOgFq1RzpExOpWTr5C77rcoHSUBOAcgagKwByKcAKv_hWXWvt3Z1ov_-eAWuj0CdeqNCisFH-2-3Kb32KSRJgbRVlPVAaummdmpYRykZejZZmx-VNmVUD_a0SuXRm2CfjLFekuk5GTxNzVplaSP7A2anr4A</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Takeuchi, Mikio</creator><creator>Niimi, Tatsuya</creator><creator>Masumoto, Mari</creator><creator>Orita, Masaya</creator><creator>Yokota, Hiroyuki</creator><creator>Yamamoto, Tomoko</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20140101</creationdate><title>Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor via in Silico Screening</title><author>Takeuchi, Mikio ; Niimi, Tatsuya ; Masumoto, Mari ; Orita, Masaya ; Yokota, Hiroyuki ; Yamamoto, Tomoko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c658t-d5bc206a0015a9e145525b3fd6fb8ebcba2ab8f0f31cfc8d580349ff9e606ba23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Computer Simulation</topic><topic>Drug Discovery - methods</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>FK866</topic><topic>Humans</topic><topic>in silico screening</topic><topic>Inhibitory Concentration 50</topic><topic>K562 Cells</topic><topic>Leukemia - drug therapy</topic><topic>Leukemia - enzymology</topic><topic>Mice</topic><topic>NAD - biosynthesis</topic><topic>Niacinamide - metabolism</topic><topic>nicotinamide adenine dinucleotide</topic><topic>Nicotinamide Mononucleotide - biosynthesis</topic><topic>nicotinamide phosphoribosyl transferase</topic><topic>Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takeuchi, Mikio</creatorcontrib><creatorcontrib>Niimi, Tatsuya</creatorcontrib><creatorcontrib>Masumoto, Mari</creatorcontrib><creatorcontrib>Orita, Masaya</creatorcontrib><creatorcontrib>Yokota, Hiroyuki</creatorcontrib><creatorcontrib>Yamamoto, Tomoko</creatorcontrib><creatorcontrib>Chiba University</creatorcontrib><creatorcontrib>Astellas Pharma Inc</creatorcontrib><creatorcontrib>Drug Discovery Research</creatorcontrib><creatorcontrib>Department of Microbiology and Molecular Genetics</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takeuchi, Mikio</au><au>Niimi, Tatsuya</au><au>Masumoto, Mari</au><au>Orita, Masaya</au><au>Yokota, Hiroyuki</au><au>Yamamoto, Tomoko</au><aucorp>Chiba University</aucorp><aucorp>Astellas Pharma Inc</aucorp><aucorp>Drug Discovery Research</aucorp><aucorp>Department of Microbiology and Molecular Genetics</aucorp><aucorp>Graduate School of Pharmaceutical Sciences</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor via in Silico Screening</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>37</volume><issue>1</issue><spage>31</spage><epage>36</epage><pages>31-36</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><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 n M , and inhibited THP-1 and K562 cell line growth with the IC50 of 198 n M and 673 n M , 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.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>24389478</pmid><doi>10.1248/bpb.b13-00495</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 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 FK866 Humans in silico screening Inhibitory Concentration 50 K562 Cells Leukemia - drug therapy Leukemia - enzymology Mice NAD - biosynthesis Niacinamide - metabolism nicotinamide adenine dinucleotide Nicotinamide Mononucleotide - biosynthesis nicotinamide phosphoribosyl transferase Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors |
| title | Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor via in Silico Screening |
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