GSK126
别名: GSK2816126A, GSK2816126
GSK126 (GSK2816126A, GSK2816126) 是一种有效的，高选择性EZH2 methyltransferase抑制剂，IC50为9.9 nM，对 EZH2 的选择性比其他20种人甲基转移酶高1000多倍。
GSK126 Chemical Structure
CAS: 1346574-57-9
产品质控
批次：
纯度：
99.91%
99.91
GSK126相关产品
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| human U2932 cells | Cytotoxic assay | 72 h | Cytotoxicity against human U2932 cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=6.7 μM. | 24767850 | |
| human PC3 cells | Cytotoxic assay | 72 h | Cytotoxicity against human PC3 cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=9.4 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 T98G cells | Cytotoxic assay | 72 h | Cytotoxicity against human T98G cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=12.6 μM. | 24767850 | |
| 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 U87MG cells | Cytotoxic assay | 72 h | Cytotoxicity against human U87MG cells assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=28.5 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 | |
| human Pfeiffer cells | Cytotoxic assay | 72 h | Cytotoxicity against human Pfeiffer cells expressing EZH2 A667G mutant assessed as growth inhibition after 72 hrs by WST-1 assay, GI50=0.18 μM. | 24767850 | |
| infected SF9 cells | Binding affinity to EZH2 (unknown origin) expressed in baculovirus infected SF9 cells co-expressing SUZ12/EED/RbAp48 complex assessed as binding off-rate at 0.4 uM incubated for 20 mins by Q-TOF mass spectrometry | 27512831 | |||
| A673 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | |||
| DAOY cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells | 29435139 | |||
| Saos-2 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | |||
| BT-37 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | |||
| RD cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells | 29435139 | |||
| SK-N-SH cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | |||
| BT-12 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells | 29435139 | |||
| MG 63 (6-TG R) cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells | 29435139 | |||
| NB1643 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | |||
| OHS-50 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | |||
| Rh41 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | |||
| SK-N-MC cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | |||
| LAN-5 cells | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | |||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | GSK126 (GSK2816126A, GSK2816126) 是一种有效的，高选择性EZH2 methyltransferase抑制剂，IC50为9.9 nM，对 EZH2 的选择性比其他20种人甲基转移酶高1000多倍。 | ||
|---|---|---|---|
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | 在体外，EZH2野生型和突变型DLBCL细胞系中，GSK126最有效地抑制H3K27me3，其次是H3K27me2。GSK126也能有效抑制EZH2突变型DLBCL细胞系的增殖，并诱导敏感细胞系中EZH2靶基因的转录激活。[1]在A687V EZH2突变细胞中，GSK126处理导致总体H3K27me3减少，强基因活化，胱天蛋白酶活化，以及增殖减少。[2]在亲代H2087细胞中，GSK126抑制VEGF-A和磷酸化Ser(473)-AK的表达，因此引起对细胞增殖，迁移和代谢的抑制。[3] | |||
|---|---|---|---|---|
| 激酶实验 | EZH2 试验 | |||
| 制备包含野生型或突变型EZH2的5个组分的PRC2复合物(Flag–EZH2，EED，SUZ12，AEBP2，RbAp48)。GSK126在DMSO中溶解，以0.6 nM到300 nM的浓度测试，终DMSO浓度为2.5%。体外实验中，相对于更倾向H3K27me0作为底物的野生型EZH2，EZH2 Y641倾向于H3K27me2作为底物，而对H3K27me0 或H3K27me1的活性很低。A677G不同于EZH2的野生型和Y641突变型，它有效地使H3K27me0，H3K27me1，和H3K27me2甲基化；因此，组蛋白H3多肽(残基21–44；终浓度10 μM)与 K27me0 (野生型，A677G EZH2)，K27me1 (A677G EZH2)，或K27me2 (A677G，Y641N，Y641C，Y641H，Y641S 和 Y641F EZH2)用作甲基转移酶底物。GSK126加入到板中，然后加入6 nM EZH2复合物和多肽。GSK126的效能处于或接近[SAM] = Km下进行的试验的紧密结合界限，IC50值在竞争性底物SMA相对其Km(7.5 μM SAM，而 SAM Km为0.3 μM)较高浓度下测量。在这些条件下，酶浓度的作用相对非常小，可以计算出Ki的精确估计值。反应通过[3H]-SAM起始，培养30分钟，加入500倍过量未标记的SAM淬灭反应，甲基化产物肽在磷酸纤维素过滤器上根据供应商提供的MSPH 多屏幕平板进行捕获。表观Ki值使用竞争性抑制剂的Cheng–Prusoff关系计算。IC50=Ki (1+[S]/Km)+[E]/2，其中E是酶，S为底物。 | ||||
| 细胞实验 | 细胞系 | 46 淋巴瘤细胞系 | ||
| 浓度 | 0~10 μM | |||
| 孵育时间 | 6天 | |||
| 方法 | 所有细胞系的最优细胞接种根据经验确定，通过检测在384孔板式中宽范围的接种密度以确定可以增殖6天的试验条件。然后细胞以最佳接种密度接种24小时，再用20点两倍连续稀释的GSK126 或0.15% DMSO处理(一式两份)。板在37℃下在5% CO2中培养6天。然后将细胞用CellTiter-Glo (CTG)裂解，化学发光信号用TECAN Safire2酶标仪检测。此外，未处理板中的细胞在化合物加入(T0)时进行采集以定量初始细胞数。处理6天后得到的CTG值表示为T0值的百分比，并以化合物浓度为横坐标绘图。数据拟合为4参数方程以产生浓度反应曲线，并测定抑制50%生长(生长 IC50)的GSK126浓度。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | H3K27Me3 / EZH2 XIAP / Survivin / MCL-1 / BID / BIM / BAX / BCL-xl/ Bcl-2 β-catenin / c-Myc / LEF1 / DVL2 / DVL3 / p-GSK3β |
|
28418882 | |
| Immunofluorescence | H3K27me3 |
|
25053977 | |
| Growth inhibition assay | Cell viability Cell proliferation |
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28418882 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | 在负荷KARPAS-422和Pfeiffer异种移植物的小鼠体内，GSK126 (150 mg/kg/d, i.p.)降低总体H3K27me3，增加基因表达，从而引起显著的肿瘤消退。[1] | |
|---|---|---|
| 动物实验 | Animal Models | 负荷 Pfeiffer 或 KARPAS-422 肿瘤的雌性米黄色 SCID 小鼠 |
| Dosages | 150 mg/kg/day | |
| Administration | i.p. | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT02082977 | Terminated | Cancer|Neoplasms |
GlaxoSmithKline |
April 24 2014 | Phase 1 |
化学信息&溶解度
| 分子量 | 526.67 | 分子式 | C31H38N6O2 |
| CAS号 | 1346574-57-9 | SDF | Download GSK126 SDF |
| Smiles | CCC(C)N1C=C(C2=C(C=C(C=C21)C3=CN=C(C=C3)N4CCNCC4)C(=O)NCC5=C(C=C(NC5=O)C)C)C | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 5 mg/mL ( (9.49 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 4 mg/mL (7.59 mM) Water : Insoluble |
摩尔浓度计算器 |
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体内溶解度 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | ||||
实验计算
动物体内配方计算器（澄清溶液）
第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于μL DMSO溶液（母液浓度mg/mL，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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常见问题及建议解决方法
问题 1:
Could you please suggest a vehicle for in vivo uses without oil?
回答：
S7061 could be dissolved in 4% DMSO+30% PEG 300+ddH2O (0.5mg/ml).
问题 2:
Does this drug require an activation step to be functional? For example, an acidic or basic environment.
回答：
GSK126 does not require an activation step to be functional.
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