A novel yeast cell-based screen identifies flavone as a tankyrase inhibitor.
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.
Yashiroda
Yoko
Y
Chemical Genomics Research Group/Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan. ytyy@riken.jp
Okamoto
Reika
R
Hatsugai
Kaori
K
Takemoto
Yasushi
Y
Goshima
Naoki
N
Saito
Tamio
T
Hamamoto
Makiko
M
Sugimoto
Yoshikazu
Y
Osada
Hiroyuki
H
Seimiya
Hiroyuki
H
Yoshida
Minoru
M
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
D004791:Enzyme Inhibitors; D047309:Flavones; D005419:Flavonoids; D038501:Tankyrases; C418109:TNKS protein, human; C043562:flavone