1346574-57-9 Usage
Biological Activity
GSK126 is an effective EZH2 methyltransferase inhibitor with IC50 being 9.9nM and high selectivity on EZH2 which is over 1000 times higher than that of the other twenty human methyltransferases.
Invitro Reaserch
GSK126 induced a 50% loss of H3K27 tri-methylation (H3K27me3) in both EZH2 wild-type and mutant DLBCL cell lines at concentrations ranging from 7–252 nM independent of EZH2 mutation status. GSK126 suppresses cell proliferation of a panel of B-cell lymphoma cell lines. Six of the seven most sensitive DLBCL cell lines harboured Y641N, Y641F or A677G EZH2 mutations (growth IC50 = 28–861 ?nM). 72?h treatment with 500?nM GSK126 induces transcriptional activation in sensitive cell lines.
Invivo Research
GSK126 treated once-daily for 10?days decreases global H3K27me3 and increases gene expression in subcutaneous xenografts of KARPAS-422 in a dose-dependent fashion. With daily 50?mg per kg dosing, complete tumour growth inhibition is observed. When higher dosing regimens are examined with KARPAS-422 xenografts, marked tumour regression is observed. Upon cessation of dosing, tumours in the 50?mg per kg once daily group shows tumour stasis whereas complete tumour eradication is observed in the 150?mg per kg once daily and 300?mg per kg twice per week groups. Tumour growth inhibition also correlates with statistically significant increased survival of mice bearing the more aggressive KARPAS-422 tumours, where spontaneous deaths occurres in vehicle-treated animals. No significant changes in any blood cell types at doses and times where efficacy is observed in tumour xenografts.
Description
The histone H3 lysine 27 (H3K27) methyltransferase EZH2 plays an important role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. GSK126 is a selective, S-adenosyl-methionine-competitive small molecule inhibitor of EZH2 methyltransferase activity (Ki = 0.57 nM; IC50 = 9.9 nM versus that of EZH1: Ki = 89 nM; IC50 = 680 nM). It is more than 1,000-fold selective for EZH2 over other histone methyltranferases, including both SET-domain-containing and non-SET-domain-containing methyltransferases. At concentrations of 7-252 nM, it has been shown to inhibit global H3K27 trimethylation levels and to reactivate silenced PRC2 target genes. Furthermore, GSK126 can inhibit the proliferation of EZH2 mutant DLBCL cell lines (IC50 = 28-61 nM) as well as the growth of EZH2 mutant DLBCL xenografts in mice receiving a daily dose of 50 mg/kg.
Uses
Different sources of media describe the Uses of 1346574-57-9 differently. You can refer to the following data:
1. GSK126 is a potent and highly selective S-adenosyl-methionine-competitive small molecule inhibitor of EZH2 methyltransferase enzyme activity. The inhibition activity of GSK126 on EZH2 activity may pro
vide a promising treatment for EZH2 mutant lymphoma.
2. GSK126 is a potent and highly selective S-adenosyl-methionine-competitive small molecule inhibitor of EZH2 methyltransferase enzyme activity. The inhibition activity of GSK126 on EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.
references
1. sato, t., et al., prc2 overexpression and prc2-target gene repression relating to poorer prognosis in small cell lung cancer. sci rep, 2013. 3(1911). 2. mccabe, m.t., et al., ezh2 inhibition as a therapeutic strategy for lymphoma with ezh2-activating mutations. nature, 2012. 492(7427): p. 108-12. 3. van aller, g.s., et al., long residence time inhibition of ezh2 in activated polycomb repressive complex 2. acs chem biol, 2014. 9(3): p. 622-9. 4. yeh, c.m., et al., epigenetic silencing of arntl, a circadian gene and potential tumor suppressor in ovarian cancer. int j oncol, 2014. 45(5): p. 2101-7.
Check Digit Verification of cas no
The CAS Registry Mumber 1346574-57-9 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,3,4,6,5,7 and 4 respectively; the second part has 2 digits, 5 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 1346574-57:
(9*1)+(8*3)+(7*4)+(6*6)+(5*5)+(4*7)+(3*4)+(2*5)+(1*7)=179
179 % 10 = 9
So 1346574-57-9 is a valid CAS Registry Number.
1346574-57-9Relevant articles and documents
New method for synthesis of EZH2 methyltransferase inhibitor GSK126
Lu, Chen,Zhang, Qiang,Chen, Xin
, p. 1215 - 1222 (2016/08/05)
GSK126 is a potent small-molecule inhibitor of S-adenosyl-methionine-competitive EZH2 methyltransferase and has the potential to be used clinically for preventing unwanted histone methylation of tumor suppressor genes. In this article, we describe a new s
METHOD OF TREATMENT
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, (2014/09/29)
The present invention relates to a method of treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases, which comprises administering to a human in need thereof an effective amount of a compound which inhibits EZH2 and/or EZH1, or a pharmaceutically acceptable salt thereof.
