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GSK461364
別名: GSK461364A
GSK461364 (GSK461364A)抑制純化的Plk1，無細胞試驗中Ki為2 nM。比作用于Plk2/3選擇性高1000倍。
GSK461364 Chemical Structure
CAS: 929095-18-1
產(chǎn)品質(zhì)控
批次：
純度：
99.97%
99.97
GSK461364相關(guān)產(chǎn)品
| 相關(guān)靶點 | PLK1 PLK2 PLK3 PLK4 | 點擊展開 |
|---|---|---|
| 相關(guān)產(chǎn)品 | BI 2536 Volasertib Rigosertib (ON-01910) Onvansertib (NMS-P937) SBE 13 HCl Ro3280 CFI-400945 HMN-214 MLN0905 Poloxin | 點擊展開 |
| 相關(guān)化合物庫 | 激酶抑制劑庫 PI3K/Akt 抑制劑庫 MAPK抑制劑庫 DNA損傷/ DNA修復(fù)化合物庫 細胞周期化合物庫 | 點擊展開 |
相關(guān)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 MV4-11 cells | Cytotoxicity assay | 24 h | Cytotoxicity against human MV4-11 cells after 24 hrs by CellTiter-Blue assay, GI50=0.679 μM | 26191363 | |
| HEK293T | Antiproliferative assay | 72 hrs | Antiproliferative activity against HEK293T cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM | 28792760 | |
| MDA-MB-231 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MDA-MB-231 cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM | 28792760 | |
| MM1S | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MM1S cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM | 28792760 | |
| MDA-MB-23 | Function assay | 6 hrs | Inhibition of PLK1 in human MDA-MB-23 cells assessed as decrease in TCTP phosphorylation after 6 hrs by Western blot method, IC50<0.1μM | 28792760 | |
| HEK293T | Function assay | 6 hrs | Inhibition of PLK1 in HEK293T cells assessed as decrease in TCTP phosphorylation after 6 hrs by Western blot method, IC50<0.1μM | 28792760 | |
| TC32 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells | 29435139 | ||
| SJ-GBM2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| BT-37 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| U-2 OS | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells | 29435139 | ||
| SK-N-SH | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| LAN-5 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| BT-12 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells | 29435139 | ||
| Rh18 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells | 29435139 | ||
| OHS-50 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells | 29435139 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells | 29435139 | ||
| BT-12 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells | 29435139 | ||
| LAN-5 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for LAN-5 cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB-EBc1 cells | 29435139 | ||
| SJ-GBM2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells | 29435139 | ||
| BT-37 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells | 29435139 | ||
| TC32 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells | 29435139 | ||
| MG 63 (6-TG R) | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells | 29435139 | ||
| fibroblast cells | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for control Hh wild type fibroblast cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells | 29435139 | ||
| Rh18 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh18 cells | 29435139 | ||
| Rh30 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells | 29435139 | ||
| OHS-50 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells | 29435139 | ||
| SK-N-SH | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells | 29435139 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | GSK461364 (GSK461364A)抑制純化的Plk1，無細胞試驗中Ki為2 nM。比作用于Plk2/3選擇性高1000倍。 | ||
|---|---|---|---|
| 特性 | GSK461364是有效的，可逆的ATP競爭性的Plk1選擇性抑制劑，作用于Plk1比作用于Plk2和Plk3選擇性至少高390倍，而比作用于一組48種其他激酶選擇性高1×103倍。 | ||
| 靶點 |
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| 體外研究(In Vitro) | ||||
| 體外研究活性 | GSK461364作用于非細胞分裂細胞，從多起點抑制癌細胞系增殖。[1] 野生型p53的RNA沉默提高GSK461364的抗增殖活性。許多癌癥療法對p53野生型患者更有效, p53缺陷腫瘤對GSK461364的高度敏感性可提供治療腫瘤的機會。GSK461364是噻吩酰胺，在體外，抑制純化的Plk1酶，Ki為2 nM，作用于Plk1比作用于 Plk2和 Plk3選擇性高100多倍。GSK461364是有效的細胞增殖抑制劑，低于100 nM 時作用于大部分細胞系，抑制50% 生長(GI50)，作用于人無增殖細胞系具有有限的毒性。GSK461364抑制細胞周期進展是濃度依賴性的，高濃度時，使細胞在G2期發(fā)生延遲，較低濃度時使細胞停在M 期。目前, GSK461364按劑量遞增方式首次用在人體試驗階段。攜帶TP53基因突變的細胞系對 GSK461364更敏感，且作用于一些p53野生型(WT)細胞，通過RNA沉默抑制p53 反應(yīng)，使敏感性增加。而且, 這些更敏感的細胞系染色體不穩(wěn)定性提高，這是與TP53突變相關(guān)的一個特點。[2] 在臨床前期研究中, GSK461364作用于多種(>120)腫瘤細胞系，具有抗增殖活性，且有效抑制這些細胞系中的 83%和91%細胞增殖，IC50分別低于50和100 nM。[3] |
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|---|---|---|---|---|
| 激酶實驗 | 酶實驗 | |||
| 使用Z-Lyte 檢測試劑盒(Ser/Thr肽 16)進行激酶反應(yīng)，終實驗體積為10 μL。反應(yīng)含50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 0.01% Brij 35, 0.01 mg/mL酪蛋白, 200 μM ATP, 200 μM Polo Box 肽 (NH2-MAGPMQS[pT]PLNGAKK-OH), 和 6 nM 重組 Plk1 (H6-tev-PLK 1-603)。Plk1與0到1×103 nM GSK461364預(yù)溫育60分鐘。加入2 μM 肽，開始反應(yīng)。在23oC下反應(yīng)15分鐘后, 反應(yīng)淬火，根據(jù)Z′-Lyte建議發(fā)法處理，然后在EnVision酶標(biāo)儀上讀數(shù)。使用底物和產(chǎn)物標(biāo)準(zhǔn)，使原料熒光值轉(zhuǎn)換為形成的產(chǎn)品濃度。隨著與ATP競爭性抑制模式相一致的ATP濃度功能變化，則觀察到GSK461364抑制效力發(fā)生變化，測定GSK461364作用的Ki最大上限值。 | ||||
| 細胞實驗 | 細胞系 | 前列腺(LNCap,PC3),子宮(HeLa),胰臟(ASPC1),肉瘤(Saos-2)，卵巢(OVCAR8),胃(NCI-N87),黑色素瘤(SKMEL3,A431,MALME3M)，結(jié)腸(Colo205,SW620,HCT116),胸腺(SKBR3,MDA-MB-453,MCF7)，肺(NCI-H82,MV522,NCI-H522)等等癌細胞系 | ||
| 濃度 | 10 nM | |||
| 孵育時間 | 72小時 | |||
| 方法 | 癌細胞系接種在384孔板上。細胞在37oC下溫育24小時。每孔加入GSK461364，濃度為10 nM。測定每組細胞系在T=0的實驗值。72小時后,從殘留細胞中抽提含GSK461364或DMSO的培養(yǎng)基，用4',6-二脒基-2-苯基吲哚進行核染色,使用 InCell1000 高通量分析儀測定熒光密度。在72小時時,計算每種濃度GSK461364在重復(fù)三次孔的每個孔中中，4',6-二脒基-2-苯基吲哚染色強度相對T=0時強度的百分數(shù)。 |
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| 實驗圖片 | 檢測方法 | 檢測指標(biāo) | 實驗圖片 | PMID |
| Western blot | p-Myt1 / Myt1 / Plk1 |
|
26597303 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | GSK461364作用于培養(yǎng)細胞的生長，可以抑制細胞生長或產(chǎn)生細胞毒性，但在適當(dāng)劑量處理下,可以導(dǎo)致移植瘤模型發(fā)生腫瘤衰退。GSK461364 作用于移植瘤模型，具有明顯的抗癌活性。[1] GSK461364作用于小鼠移植瘤，使細胞周期停滯，這種作用存在劑量依賴性，與作用于腫瘤生長相關(guān)。[2] GSK461364腹腔注射處理不同移植瘤模型，包括Colo205移植瘤，導(dǎo)致衰退或腫瘤生長延遲。在體內(nèi)，使用GSK461364抑制Plk1，導(dǎo)致有絲分裂停滯，形成由單極或倒塌的有絲分裂紡錘體組成的異常有絲分裂。[3] |
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|---|---|---|
| 動物實驗 | Animal Models | 攜帶結(jié)腸Colo205移植瘤的裸鼠 |
| Dosages | 25, 50, 和100 mg/kg | |
| Administration | 腹膜注射，每隔2天或4天進行。 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00536835 | Completed | Lymphoma Non-Hodgkin |
GlaxoSmithKline |
August 16 2007 | Phase 1 |
化學(xué)信息&溶解度
| 分子量 | 543.6 | 分子式 | C27H28F3N5O2S |
| CAS號 | 929095-18-1 | SDF | Download GSK461364 SDF |
| Smiles | CC(C1=CC=CC=C1C(F)(F)F)OC2=C(SC(=C2)N3C=NC4=C3C=C(C=C4)CN5CCN(CC5)C)C(=O)N | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
Ethanol : 30 mg/mL (55.18 mM) DMSO : 10 mg/mL ( (18.39 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Water : Insoluble |
摩爾濃度計算器 |
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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:
I would like to know whether the recommended in vivo formulation will be suitable for i.p. injections
回答：
GSK461364 in 1% DMSO+30% polyethylene glycol+1% Tween 80 at 30mg/ml is a suspension, and it is fine for oral gavage.
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