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Trans. R. Soc. B"],"published-print":{"date-parts":[[2018,6,5]]},"abstract":"<jats:p>\n                    SIRT2 is a member of the human sirtuin family of proteins and possesses NAD\n                    <jats:sup>+<\/jats:sup>\n                    -dependent lysine deacetylase\/deacylase activity. SIRT2 has been implicated in carcinogenesis in various cancers including leukaemia and is considered an attractive target for cancer therapy. Here, we identified NPD11033, a selective small-molecule SIRT2 inhibitor, by a high-throughput screen using the RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins and zinc-dependent deacetylases. Crystallographic analysis revealed a unique mode of action, in which NPD11033 creates a hydrophobic cavity behind the substrate-binding pocket after a conformational change of the Zn-binding small domain of SIRT2. Furthermore, it forms a hydrogen bond to the active site histidine residue. In addition, NPD11033 inhibited cell growth of human pancreatic cancer PANC-1 cells with a concomitant increase in the acetylation of eukaryotic translation initiation factor 5A, a physiological substrate of SIRT2. Importantly, NPD11033 failed to inhibit defatty-acylase activity of SIRT2, despite its potent inhibitory effect on its deacetylase activity. Thus, NPD11033 will serve as a useful tool for both developing novel anti-cancer agents and elucidating the role of SIRT2 in various cellular biological processes.\n                  <\/jats:p>\n                  <jats:p>This article is part of a discussion meeting issue \u2018Frontiers in epigenetic chemical biology\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2017.0070","type":"journal-article","created":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T03:35:13Z","timestamp":1524454513000},"page":"20170070","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":54,"title":["Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2"],"prefix":"10.1098","volume":"373","author":[{"given":"Norio","family":"Kudo","sequence":"first","affiliation":[{"name":"Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Arata","sequence":"additional","affiliation":[{"name":"Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Nakata","sequence":"additional","affiliation":[{"name":"Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4376-5674","authenticated-orcid":false,"given":"Minoru","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Tokyo 113-8657, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2018,4,23]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.2183\/pjab.93.019"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1412706"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00038-8"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00304.x"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.07.003"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.073783"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.02.005"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-3615"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2498"},{"key":"e_1_3_6_11_2","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.15252\/embj.201386907","article-title":"SIRT2 induces the checkpoint kinase BubR1 to increase lifespan","volume":"33","author":"North BJ","year":"2014","journal-title":"EMBO J."},{"key":"e_1_3_6_12_2","first-page":"819","article-title":"HDAC6 and SIRT2 promote bladder cancer cell migration and invasion by targeting cortactin","volume":"27","author":"Zuo Q","year":"2012","journal-title":"Oncol. 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