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CAS No.: 1346574-57-9

GSK126 Catalog No. CSN13635

Synonyms: GSK2816126A;EZH2 Inhibitor;GSK-2816126

GSK126 is a potent, highly selective EZH2 methyltransferase inhibitor with IC50 of 9.9 nM, > 1000-fold selective for EZH2 over 20 other human methyltransferases.

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400-920-2911

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 EZH2

IC50:9.9nM
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 (Ki^app=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 (Ki^app = 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

Cell Data

Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
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

动物研究

剂量

Mice: 2.5 mg/kg^[2] (i.v.); min = 125 mg/kg, max = 1000 mg/kg^[3] (p.o.)

给药途径

i.v., p.o.

动物药代数据

Animal	Rats^[4]
Dose	50 mg/kg
Administration	p.o.
C_max	155.6 ± 42.4 ng/ml
T_max	0.25 h
AUC_0→∞	636.3 ± 82.0 h·ng/ml
T_β	10.7 ± 3.2 h

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

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.8987 mL
- 9.4936 mL
- 18.9871 mL
- 5 mM
- 0.3797 mL
- 1.8987 mL
- 3.7974 mL
- 10 mM
- 0.1899 mL
- 0.9494 mL
- 1.8987 mL

技术信息

CAS号

1346574-57-9

储存条件

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

液体: -20°C:3-6 月 -80°C:12月

分子式

C31H38N6O2

运输

蓝冰

分子量

526.67

别名

GSK2816126A;EZH2 Inhibitor;GSK-2816126

溶解度

DMSO	5.0 mg/mL (9.5 mM) warming
Water	insoluble

动物实验配方

IP	5% DMSO+water	0.8 mg/mL	clear
PO	0.5% CMC-Na	48 mg/mL	suspension

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