2. Academic Validation
  3. Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors

Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors

  • Bioorg Med Chem Lett. 2014 Jun 1;24(11):2486-92. doi: 10.1016/j.bmcl.2014.04.010.
Jimin Woo 1,  Hyun-Young Kim 2,  Byung Jin Byun 2,  Chong-Hak Chae 2,  Ji Young Lee 3,  Shi Yong Ryu 3,  Woo-Kyu Park 2,  Heeyeong Cho 4,  Gildon Choi 5
Affiliations

Affiliations

  • 1 Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology, Gajeong-Ro 141, Yuseong-gu, Daejeon 305-600, Republic of Korea; Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Gajeong-Ro 217, Yuseong-gu, Daejeon 305-350, Republic of Korea.
  • 2 Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology, Gajeong-Ro 141, Yuseong-gu, Daejeon 305-600, Republic of Korea.
  • 3 Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology, Gajeong-Ro 141, Yuseong-gu, Daejeon 305-600, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daehak-ro 79, Yuseong-gu, Daejeon 305-764, Republic of Korea.
  • 4 Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology, Gajeong-Ro 141, Yuseong-gu, Daejeon 305-600, Republic of Korea; Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Gajeong-Ro 217, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: hycho@krict.re.kr.
  • 5 Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology, Gajeong-Ro 141, Yuseong-gu, Daejeon 305-600, Republic of Korea; Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Gajeong-Ro 217, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: gchoi@krict.re.kr.
PMID: 24767850 DOI: 10.1016/j.bmcl.2014.04.010
Abstract

EZH2 is the core subunit of Polycomb repressive complex 2 catalyzing the methylation of histone H3 lysine-27 and closely involved in tumorigenesis. To discover small molecule inhibitors for EZH2 methyltransferase activity, we performed an inhibitor screen with catalytically active EZH2 protein complex and identified tanshindiols as EZH2 inhibitors. Tanshindiol B and C potently inhibited the methyltransferase activity in in vitro enzymatic assay with IC50 values of 0.52μM and 0.55μM, respectively. Tanshindiol C exhibited growth inhibition of several Cancer cells including Pfeiffer cell line, a diffuse large B cell lymphoma harboring EZH2 A677G activating mutation. Tanshindiol treatment in Pfeiffer cells significantly decreased the tri-methylated form of histone H3 lysine-27, a substrate of EZH2, as revealed by Western blot analysis and histone methylation ELISA. Based on Enzyme kinetics and docking studies, we propose that tanshindiol-mediated inhibition of EZH2 activity is competitive for the substrate S-adenosylmethionine. Taken together, our findings strongly suggest that tanshindiols possess a unique anti-cancer activity whose mechanism involves the inhibition of EZH2 activity and would provide chemically valuable information for designing a new class of potent EZH2 inhibitors.

Keywords

EZH2; Histone methyltransferase; Tanshindiol; Tanshinone.

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