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GSK126
別名: GSK2816126A, GSK2816126
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。
GSK126 Chemical Structure
CAS: 1346574-57-9
產(chǎn)品質(zhì)控
批次：
純度：
99.91%
99.91
GSK126相關產(chǎn)品
相關信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| 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 | |||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | 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 |
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| 體外研究(In Vitro) | ||||
| 體外研究活性 | 在體外，EZH2野生型和突變型DLBCL細胞系中，GSK126最有效地抑制H3K27me3，其次是H3K27me2。GSK126也能有效抑制EZH2突變型DLBCL細胞系的增殖，并誘導敏感細胞系中EZH2靶基因的轉(zhuǎn)錄激活。[1]在A687V EZH2突變細胞中，GSK126處理導致總體H3K27me3減少，強基因活化，胱天蛋白酶活化，以及增殖減少。[2]在親代H2087細胞中，GSK126抑制VEGF-A和磷酸化Ser(473)-AK的表達，因此引起對細胞增殖，遷移和代謝的抑制。[3] | |||
|---|---|---|---|---|
| 激酶實驗 | EZH2 試驗 | |||
| 制備包含野生型或突變型EZH2的5個組分的PRC2復合物(Flag–EZH2，EED，SUZ12，AEBP2，RbAp48)。GSK126在DMSO中溶解，以0.6?nM到300?nM的濃度測試，終DMSO濃度為2.5%。體外實驗中，相對于更傾向H3K27me0作為底物的野生型EZH2，EZH2 Y641傾向于H3K27me2作為底物，而對H3K27me0 或H3K27me1的活性很低。A677G不同于EZH2的野生型和Y641突變型，它有效地使H3K27me0，H3K27me1，和H3K27me2甲基化；因此，組蛋白H3多肽(殘基21–44；終濃度10?μM)與 K27me0 (野生型，A677G EZH2)，K27me1 (A677G EZH2)，或K27me2 (A677G，Y641N，Y641C，Y641H，Y641S 和 Y641F EZH2)用作甲基轉(zhuǎn)移酶底物。GSK126加入到板中，然后加入6?nM EZH2復合物和多肽。GSK126的效能處于或接近[SAM] = Km下進行的試驗的緊密結(jié)合界限，IC50值在競爭性底物SMA相對其Km(7.5 μM SAM，而 SAM Km為0.3?μM)較高濃度下測量。在這些條件下，酶濃度的作用相對非常小，可以計算出Ki的精確估計值。反應通過[3H]-SAM起始，培養(yǎng)30分鐘，加入500倍過量未標記的SAM淬滅反應，甲基化產(chǎn)物肽在磷酸纖維素過濾器上根據(jù)供應商提供的MSPH 多屏幕平板進行捕獲。表觀Ki值使用競爭性抑制劑的Cheng–Prusoff關系計算。IC50=Ki (1+[S]/Km)+[E]/2，其中E是酶，S為底物。 | ||||
| 細胞實驗 | 細胞系 | 46 淋巴瘤細胞系 | ||
| 濃度 | 0~10 μM | |||
| 孵育時間 | 6天 | |||
| 方法 | 所有細胞系的最優(yōu)細胞接種根據(jù)經(jīng)驗確定，通過檢測在384孔板式中寬范圍的接種密度以確定可以增殖6天的試驗條件。然后細胞以最佳接種密度接種24小時，再用20點兩倍連續(xù)稀釋的GSK126 或0.15% DMSO處理(一式兩份)。板在37℃下在5% CO2中培養(yǎng)6天。然后將細胞用CellTiter-Glo (CTG)裂解，化學發(fā)光信號用TECAN Safire2酶標儀檢測。此外，未處理板中的細胞在化合物加入(T0)時進行采集以定量初始細胞數(shù)。處理6天后得到的CTG值表示為T0值的百分比，并以化合物濃度為橫坐標繪圖。數(shù)據(jù)擬合為4參數(shù)方程以產(chǎn)生濃度反應曲線，并測定抑制50%生長(生長 IC50)的GSK126濃度。 |
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| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | 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 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | 在負荷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，從而引起顯著的腫瘤消退。[1] | |
|---|---|---|
| 動物實驗 | Animal Models | 負荷 Pfeiffer 或 KARPAS-422 腫瘤的雌性米黃色 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 |
化學信息&溶解度
| 分子量 | 526.67 | 分子式 | C31H38N6O2 |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 5 mg/mL ( (9.49 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Ethanol : 4 mg/mL (7.59 mM) Water : Insoluble |
摩爾濃度計算器 |
|
體內(nèi)溶解度 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內(nèi)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結(jié)果：
工作液濃度： mg/ml；
DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。
體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。
注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。
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常見問題及建議解決方法
問題 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).
問題 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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