title: A novel yeast cell-based screen identifies flavone as a tankyrase inhibitor.
abstract: The telomere-associated protein tankyrase 1 is a poly(ADP-ribose) polymerase and is considered to be a promising target for cancer therapy, especially for BRCA-associated cancers. However, an efficient assay system for inhibitor screening has not been established, mainly due to the difficulty of efficient preparation of the enzyme and its substrate. Here, we report a cell-based assay system for detecting inhibitory activity against tankyrase 1. We found that overexpression of the human tankyrase 1 gene causes a growth defect in the fission yeast Schizosaccharomyces pombe. Chemicals that restore the growth defect phenotype can be identified as potential tankyrase 1 inhibitors. We performed a high-throughput screen using this system, and identified flavone as a compound that restores the growth of yeast cells overexpressing tankyrase 1. Indeed, flavone inhibited poly(ADP-ribosyl)ation of proteins caused by overexpression of tankyrase 1 in yeast cells. This system allows rapid identification of inhibitory activity against tankyrase 1 and is amenable to high-throughput screening using robotics.
authors.affiliation: Chemical Genomics Research Group/Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan. ytyy@riken.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yashiroda
authors.forename: Reika
authors.initials: R
authors.lastname: Okamoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Hatsugai
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takemoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Goshima
authors.forename: Tamio
authors.initials: T
authors.lastname: Saito
authors.forename: Makiko
authors.initials: M
authors.lastname: Hamamoto
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D002460:Cell Line; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D047309:Flavones; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D047309:Flavones; D005419:Flavonoids; D038501:Tankyrases; C418109:TNKS protein, human; C043562:flavone