Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects

Choi,Gildon; Lee,Jongkook; Ji,Jeong  Yeon; Woo,Jimin; Kang,Nam  Sook; Cho,Sung   Yun; Kim,Hyoung   Rae; Ha,Jae  Du; Han,Sun-Young

doi:10.3892/ijo.2013.2035

Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects

Authors:
- Gildon Choi
- Jongkook Lee
- Jeong Yeon Ji
- Jimin Woo
- Nam Sook Kang
- Sung Yun Cho
- Hyoung Rae Kim
- Jae Du Ha
- Sun-Young Han
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Affiliations: Korea Research Institute of Chemical Technology and University of Science and Technology (UST), Daejeon, Republic of Korea, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea, Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea
Published online on: July 23, 2013 https://doi.org/10.3892/ijo.2013.2035
Pages: 1205-1211

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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 GI50 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.

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