Background
EPZ-6438 is a potent and bio-available inhibitor of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2) catalyzing the methylation of lysine 27 of histone H3 (H3K27), that inhibits the activity of human PRC2-containing wild-type EZH2 with a value of inhibition constant Ki of 2.5 nM. EPZ-6438 competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and also non-competitively binds to the binding sites of peptide or nucleosome substrate. EPZ-6438 selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that EPZ-6438 exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of EPZ-6438-mediated EZH2 inhibition on several cancer pathways.
EPZ-6438 是一种有效且具有生物利用度的 EZH2 抑制剂，EZH2 是多梳抑制复合物 2 (PRC2) 的催化亚基，可催化组蛋白 H3 (H3K27) 的赖氨酸 27 甲基化，从而抑制含有人 PRC2 的活性抑制常数 Ki 值为 2.5 nM 的野生型 EZH2。 EPZ-6438 竞争性结合 EZH2 的 S-腺苷甲硫氨酸 (SAM) 结合位点，也非竞争性结合肽或核小体底物的结合位点。 EPZ-6438 选择性抑制 EZH2，选择性比 EZH1 高 35 倍。研究结果表明，EPZ-6438 通过 EPZ-6438 介导的 EZH2 抑制对多种癌症通路的协同作用，在 MRT 模型中表现出显着和永久的抗肿瘤活性。
Reference
[1].Sarah K. Knutson1, Natalie M. Warholic, Tim J. Wigle, Christine R. Klaus, Christina J. Allain, Alejandra Raimondi, Margaret Porter Scott, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, Roy M. Pollock, Kevin W. Kuntz, and Heike Keilhack. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 2013; 110(19): 7922-7927
Protocol
| Cell experiment [1]: |
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Cell lines
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SMARCB1-deficient MRT cells
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Preparation method
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Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reaction Conditions
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4-7 days
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Applications
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EPZ-6438 induces a reduction of global H3K27Me3 level in a concentration-dependent manner. In addition, EPZ-6438 leads to a substantial antiproliferative effects as IC50 values within nanomolar range. Treatment of EPZ-6438 results in expression of CD133, DOCK4, and PTPRK and up-regulates CDKN1A and CDKN2A and BIN1in a time-dependent manner.
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| Animal experiment [2]: |
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Animal models
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SCID mice bearing EZH2-mutant lymphoma xenografts.
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Dosage form
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3 times daily every 8 hours, 2 times a day every 12 hours, or once a day schedules for either 7 or 28 days by oral gavage.
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Applications
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EPZ-6438 dose-dependently causes a reduction of tumor H3K27Me3 levels (EC50 =23 nmol/L). EPZ-6438 also shows a remarkable antitumor effects in a dose dependent manner with 2 cycles of 7-day on/7-day off and 21-day on/7-day off schedules. All EPZ-6438 dose groups except the lowest one leads to complete tumor regressions.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
1. Knutson SK, Warholic NM, Wigle TJ et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7.
2. Knutson SK, Kawano S, Minoshima Y et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54.
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