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GSK126

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Chemical Structure| 1346574-57-9 同义名 : GSK2816126A;GSK2816126
CAS号 : 1346574-57-9
货号 : A114568
分子式 : C31H38N6O2
纯度 : 99%+
分子量 : 526.672
MDL号 : MFCD23381067
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 12 mg/mL(22.78 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 5% DMSO+water 0.8 mg/mL clear

PO 0.5% CMC-Na 48 mg/mL suspension

生物活性
靶点

  • Histone Methyltransferase

    EZH2, IC50:9.9 nM
描述 EZH2 is the enzymatic subunit of PRC2 (Polycomb repressive complex 2), a complex that can methylate lysine 27 of histone H3 (H3K27) to promote transcriptional silencing. GSK126 is a potent inhibitor of EZH2 and inhibits both wild-type and mutant EZH2 methyltransferase activity with similar potencies (Kiapp=0.5 - 3 nM, measure by enzymatic activity) and has more than 1,000-fold selectivity for EZH2 as compared with other methyltransferases and 150-fold as compared to EZH1 (Kiapp = 89 nM). GSK126 induced a 50% loss of H3K27me3 in both EZH2 wild-type and mutant DLBCL cell lines at concentrations ranging from 7 - 252 nM independent of EZH2 mutation status (treated with GSK126 for 48h). GSK126 most potently inhibited H3K27me3, followed by H3K27me2 and H3K27me1 were only weakly reduced at the highest inhibitor concentration, with no effect on total histone H3 and PRC2 components. Following 10 days of once-daily dosing of GSK126 in mice using subcutaneous xenografts of KARPAS-422 and Pfeiffer cells, on dose 15 - 150 mg/kg, global H3K27me3 decreased and EZH2 targeted genes (TXNIP and TNFRSF21) expression increased in a dose dependent fashion. With daily 50 mg/kg dosing, complete tumor growth inhibition can be observed in both KARPAS-422 and Pfeiffer cell models. Complete tumor eradication can be observed on dose of 150 mg/kg daily or 300 mg/kg twice a week[1].
作用机制 GSK126 is the SAM-competitive inhibitor of PRC2[1].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human A549 cells Cytotoxic assay 72 h Cytotoxicity against human A549 cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=18.7 μM. 24767850
human Daudi cells Cytotoxic assay 72 h Cytotoxicity against human Daudi cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=11.2 μM. 24767850
human HeLa cells Function assay 72 h Inhibition of EZH2 in human HeLa cells assessed as reduction in H3K27me3 levels incubated for 72 hrs by ELISA method, IC50=0.28 μM. 26189078
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.90mL

0.38mL

0.19mL

9.49mL

1.90mL

0.95mL

18.99mL

3.80mL

1.90mL
参考文献

[1]McCabe MT, Ott HM, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012 Dec 6;492(7427):108-12.

[2]Zhang P, de Gooijer MC, et al. ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors. Int J Cancer. 2015 Oct 15;137(8):2007-18.

[3]Campbell JE, Kuntz KW, et al. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett. 2015 Mar 4;6(5):491-5.

[4]EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies