PF-06726304
目录号 : GC32977
PF-06726304是有效，选择性的EZH2抑制剂，Ki值为0.7nM。
Cas No.:1616287-82-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | PF-06726304 dilutions are prepared. Karpas-422 cells are treated with PF-06726304. Cell Growth Inhibition is performed and IC50 values are calculated[1]. |
Animal experiment: | Mice: Mice are treated with PF-06726304 at 200 and 300 mg/kg BID for 20 days. Tumor growth is monitored for several weeks following cessation of dosing. Average body weight is measured during the duration of compound treatment. Global H3K27Me3 levels are measured in Karpas-422 tumors harvested on day 20[1]. |
References: [1]. Kung PP, et al. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. J Med Chem. 2016 Sep 22;59(18):8306-25. | |
PF-06726304 is a potent and selective EZH2 inhibitor with a Ki of 0.7 nM.
PF-06726304 displays potent biochemical and cellular potencies in the Karpas-422 cell line. Upon treatment with PF-06726304 for 7 days, both TNFRSF21 and PRDM1 are upregulated in Karpas-422 cells containing both wild-type and Y641N mutant EZH2 proteins in a dose-dependent manner[1].
PF-06726304 inhibits tumor growth and induces robust modulation of downstream biomarkers in a Karpas-422 in vivo model. Treatment with PF-06726304 is well-tolerated at 200 and 300 mg/kg in mice, with less than 10% body weight loss observed during the course of the experiment. on day 20, PF-06726304 demonstrates tumor stasis and regression at the 200 and 300 mg/kg dose levels, respectively. In addition, tumor growth inhibition is sustained for at least another 3 weeks after the last dose, demonstrating the ability of PF-06726304 to mediate long-term epigenetic reprogramming in cells. PF-06726304 induces approximately 55.5% and 66.4% reduction of the H3K27Me3 level at doses of 200 and 300 mg/kg, respectively. In addition, the PRC2 target genes TNFRSF21 and PRDM1 are both strongly upregulated in both the 200 and 300 mg/kg dosing arms[1].
[1]. Kung PP, et al. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. J Med Chem. 2016 Sep 22;59(18):8306-25.
| Cas No. | 1616287-82-1 | SDF | |
| Canonical SMILES | O=C1N(CC2=C(C)C=C(C)NC2=O)CCC3=C1C(Cl)=C(C4=C(C)ON=C4C)C=C3Cl | ||
| 分子式 | C22H21Cl2N3O3 | 分子量 | 446.33 |
| 溶解度 | DMSO : ≥ 15 mg/mL (33.61 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2405 mL | 11.2025 mL | 22.4049 mL |
| 5 mM | 0.4481 mL | 2.2405 mL | 4.481 mL |
| 10 mM | 0.224 mL | 1.1202 mL | 2.2405 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Inhibition of methyltransferase activity of enhancer of zeste 2 leads to enhanced lipid accumulation and altered chromatin status in zebrafish
Epigenetics Chromatin 2020 Feb 12;13(1):5.PMID:32051014DOI:PMC7014624
Background: Recent studies indicate that exposure to environmental chemicals may increase susceptibility to developing metabolic diseases. This susceptibility may in part be caused by changes to the epigenetic landscape which consequently affect gene expression and lead to changes in lipid metabolism. The epigenetic modifier enhancer of zeste 2 (Ezh2) is a histone H3K27 methyltransferase implicated to play a role in lipid metabolism and adipogenesis. In this study, we used the zebrafish (Danio rerio) to investigate the role of Ezh2 on lipid metabolism and chromatin status following developmental exposure to the Ezh1/2 inhibitor PF-06726304 acetate. We used the environmental chemical tributyltin (TBT) as a positive control, as this chemical is known to act on lipid metabolism via EZH-mediated pathways in mammals. Results: Zebrafish embryos (0-5 days post-fertilization, dpf) exposed to non-toxic concentrations of PF-06726304 acetate (5 μM) and TBT (1 nM) exhibited increased lipid accumulation. Changes in chromatin were analyzed by the assay for transposase-accessible chromatin sequencing (ATAC-seq) at 50% epiboly (5.5 hpf). We observed 349 altered chromatin regions, predominantly located at H3K27me3 loci and mostly more open chromatin in the exposed samples. Genes associated to these loci were linked to metabolic pathways. In addition, a selection of genes involved in lipid homeostasis, adipogenesis and genes specifically targeted by PF-06726304 acetate via altered chromatin accessibility were differentially expressed after TBT and PF-06726304 acetate exposure at 5 dpf, but not at 50% epiboly stage. One gene, cebpa, did not show a change in chromatin, but did show a change in gene expression at 5 dpf. Interestingly, underlying H3K27me3 marks were significantly decreased at this locus at 50% epiboly. Conclusions: Here, we show for the first time the applicability of ATAC-seq as a tool to investigate toxicological responses in zebrafish. Our analysis indicates that Ezh2 inhibition leads to a partial primed state of chromatin linked to metabolic pathways which results in gene expression changes later in development, leading to enhanced lipid accumulation. Although ATAC-seq seems promising, our in-depth assessment of the cebpa locus indicates that we need to consider underlying epigenetic marks as well.