1346574-57-9
中文名稱
GSK126
英文名稱
S)-1-(sec-butyl)-N-((4,6-diMethyl-2-oxo-1,2-dihydropyridin-3-yl)Methyl)-3-Methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxaMide
CAS
1346574-57-9
分子式
C31H38N6O2
分子量
526.672
MOL 文件
1346574-57-9.mol
更新日期
2024/12/20 09:35:54
1346574-57-9 結(jié)構(gòu)式
基本信息
中文別名
GSK126CPDB1065
GSK126
GSK-126
GSK 126
英文別名
GSK-2816126GSK126, >=98%
N-[(4,6-Dimethyl-2-ox
1-(S)-sec-butyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide
S)-1-(sec-butyl)-N-((4,6-diMethyl-2-oxo-1,2-dihydropyridin-3-yl)Methyl)-3-Methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxaMide
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide GSK126
GSK 126 N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide
所屬類別
生物化工：Histone Methyltransferase 抑制劑物理化學(xué)性質(zhì)
熔點>216°C (dec.)
沸點823.4±65.0 °C(Predicted)
密度1.25±0.1 g/cm3(Predicted)
儲存條件-20°C冷凍
溶解度可溶于DMSO（輕微）、甲醇（輕微、加熱）
酸度系數(shù)(pKa)11.93±0.10(Predicted)
形態(tài)固體
顏色米白色
常見問題列表
生物活性
GSK126 是一種有效的，高選擇性EZH2 methyltransferase抑制劑，IC50為9.9 nM，對 EZH2 的選擇性比其他20種人甲基轉(zhuǎn)移酶高1000多倍。體外研究
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.體內(nèi)研究
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.生物活性
GSK126 (GSK2816126A, GSK2816126) 是一種有效的，高選擇性EZH2 methyltransferase抑制劑，IC50為9.9 nM，對 EZH2 的選擇性比其他20種人甲基轉(zhuǎn)移酶高1000多倍。靶點
| Target | Value |
|
EZH2
(Cell-free assay) | 9.9 nM |
體外研究
在體外，EZH2野生型和突變型DLBCL細(xì)胞系中，GSK126最有效地抑制H3K27me3，其次是H3K27me2。GSK126也能有效抑制EZH2突變型DLBCL細(xì)胞系的增殖，并誘導(dǎo)敏感細(xì)胞系中EZH2靶基因的轉(zhuǎn)錄激活。在A687V EZH2突變細(xì)胞中，GSK126處理導(dǎo)致總體H3K27me3減少，強基因活化，胱天蛋白酶活化，以及增殖減少。在親代H2087細(xì)胞中，GSK126抑制VEGF-A和磷酸化Ser(473)-AK的表達(dá)，因此引起對細(xì)胞增殖，遷移和代謝的抑制。
體內(nèi)研究
在負(fù)荷KARPAS-422和Pfeiffer異種移植物的小鼠體內(nèi)，GSK126 (150 mg/kg/d, i.p.)降低總體H3K27me3，增加基因表達(dá)，從而引起顯著的腫瘤消退。