کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10592130 | 981777 | 2014 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors
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کلمات کلیدی
IC50EZH2SUZ12EEDGI50tanshinone - تانشینونELISA - تست الیزاEnzyme-linked immunosorbent assay - تست الیزاenhancer of zeste homologue 2 - تقویت کننده پوست پوستی 2embryonic ectoderm development - توسعه اکو تروم جنینhalf maximal inhibitory concentration - نیمه حداکثر غلظت مهاریHistone Methyltransferase - هیستون متیل ترانسفراز
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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 0.52 μM and 0.55 μM, 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 11, 1 June 2014, Pages 2486-2492
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 11, 1 June 2014, Pages 2486-2492
نویسندگان
Jimin Woo, Hyun-Young Kim, Byung Jin Byun, Chong-Hak Chae, Ji Young Lee, Shi Yong Ryu, Woo-Kyu Park, Heeyeong Cho, Gildon Choi,