title: Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity.
abstract: SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro. The compound increased the acetylation level of eukaryotic translation initiation factor 5A (eIF5A), a physiological substrate of SIRT2, and reduced cell viability of human breast cancer cells accompanied with a decrease in c-Myc expression. These results suggest that the compound is cellular effective and has potential for development as a therapeutic agent against breast cancers by specific inhibition of SIRT2.
authors.affiliation: Chemical Genetics Laboratory, RIKEN.
authors.forename: Asad Ali
authors.initials: AA
authors.lastname: Shah
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakata
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009711:Nucleotides / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D009711:Nucleotides; C000613647:RK-9123016; D009536:Niacinamide; C474199:SIRT2 protein, human; D056565:Sirtuin 2