GSK126 is a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity. GSK126 decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice.
|Cell lines||EZH2 wildtype or mutant B-cell lymphoma cell lines|
|Preparation method||Cell proliferation assay. The optimal cell seeding was determined empirically for all cell lines by examining the growth of a wide range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 6 days. Cells were then plated at the optimal seeding density 24 h before treatment (in duplicate) with a 20-point twofold dilution series of GSK126 or 0.15% DMSO. Plates were incubated for 6 days at 37℃ in 5% CO2. Cells were then lysed with CellTiter-Glo (CTG) (Promega) and chemiluminescent signal was detected with a TECAN Safire2 microplate reader. In addition, an untreated plate of cells was harvested at the time of compound addition (T0) to quantify the starting number of cells. CTG values obtained after the 6 day treatment were expressed as a percent of the T0 value and plotted against compound concentration. Data were fit with a four-parameter equation to generate a concentration response curve and the concentration of GSK126 required to inhibit 50% of growth (growth IC50) was determined.|
|Incubation time||6 days|
|Animal models||Pfeiffer or KARPAS-422 cells tumour xenograft in mice|
|Formulation||20% captisol adjusted to pH 4–4.5 with 1 N acetic acid.|
|Dosages||0.2 ml per 20 g body weight|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 50 mg/mL|
|Source||Oncotarget (2017). Figure 2. GSK126|
|Cell Lines||multiple myeloma cells|
|Incubation Time||24 h|
|Results||The results showed that after exposure to GSK126 for 24 h, the colonyformation ability of MM cells were significantly reduced with IC50 < 10 μM|
PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer.
Sato T, et al. Sci Rep. 2013;3:1911. PMID: 23714854.
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
McCabe MT, et al. Nature. 2012 Dec 6;492(7427):108-12. PMID: 23051747.
|Related EZH2 Products|
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GSK343 is a potent and selective EZH2 inhibitor with IC50 of 4 nM, showing 60 fold selectivity against EZH1, and >1000 fold selectivity against other histone methyltransferases.
EPZ-6438 is a potent, and selective EZH2 inhibitor with Ki and IC50 of 2.5 nM and 11 nM, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.
EPZ005687 is a potent and selective inhibitor of EZH2 with Ki of 24 nM, 50-fold selectivity against EZH1 and 500-fold selectivity against 15 other protein methyltransferases.
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