title: Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects.
abstract: SIRT1 and SIRT2 are deacetylase enzymes that belong to the sirtuin family and are involved in tumorigenesis. In our screen for small molecules inhibiting SIRT1/2 toxoflavin was identified. Toxoflavin potently inhibited SIRT1 activity in in vitro deacetylase assay using purified SIRT1 protein. SIRT2 activity was also inhibited by toxoflavin less potently than SIRT1 in deacetylase assay in vitro. Toxoflavin exhibited growth inhibition of various cancer cell lines including A549 lung cancer cells with a GI(50) of 48 nM. Toxoflavin treatment in A549 cells increased the acetylated form of p53, which is a substrate of SIRT1. The acetylation levels of α-tubulin, a SIRT2 substrate, were also increased by toxoflavin treatment dose-dependently. Several toxoflavin derivatives were synthesized to determine the preliminary structure-activity relationship of toxoflavin. Some of the toxoflavin derivatives showed highly selective inhibition against SIRT1. In conclusion, this study presented toxoflavin as a potent SIRT1/2 inhibitor with anticancer activity.
authors.affiliation: Korea Research Institute of Chemical Technology and University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Gildon
authors.initials: G
authors.lastname: Choi
authors.forename: Jongkook
authors.initials: J
authors.lastname: Lee
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Ji
authors.forename: Jimin
authors.initials: J
authors.lastname: Woo
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Han
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001549:Benzamides; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011744:Pyrimidinones / Q000008:administration & dosage; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D054852:Small Molecule Libraries / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage; D014404:Tubulin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D011744:Pyrimidinones; D054852:Small Molecule Libraries; D014227:Triazines; D014404:Tubulin; C009570:toxoflavin; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2