GSK461364
别名: GSK461364A
GSK461364 (GSK461364A)抑制纯化的Plk1，无细胞试验中Ki为2 nM。比作用于Plk2/3选择性高1000倍。
GSK461364 Chemical Structure
CAS: 929095-18-1
产品质控
批次：
纯度：
99.97%
99.97
GSK461364相关产品
| 相关靶点 | PLK1 PLK2 PLK3 PLK4 | 点击展开 |
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| 相关化合物库 | 激酶抑制剂库 PI3K/Akt 抑制剂库 MAPK抑制剂库 DNA损伤/ DNA修复化合物库 细胞周期化合物库 | 点击展开 |
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 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 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | GSK461364 (GSK461364A)抑制纯化的Plk1，无细胞试验中Ki为2 nM。比作用于Plk2/3选择性高1000倍。 | ||
|---|---|---|---|
| 特性 | GSK461364是有效的，可逆的ATP竞争性的Plk1选择性抑制剂，作用于Plk1比作用于Plk2和Plk3选择性至少高390倍，而比作用于一组48种其他激酶选择性高1×103倍。 | ||
| 靶点 |
|
| 体外研究(In Vitro) | ||||
| 体外研究活性 | GSK461364作用于非细胞分裂细胞，从多起点抑制癌细胞系增殖。[1] 野生型p53的RNA沉默提高GSK461364的抗增殖活性。许多癌症疗法对p53野生型患者更有效, p53缺陷肿瘤对GSK461364的高度敏感性可提供治疗肿瘤的机会。GSK461364是噻吩酰胺，在体外，抑制纯化的Plk1酶，Ki为2 nM，作用于Plk1比作用于 Plk2和 Plk3选择性高100多倍。GSK461364是有效的细胞增殖抑制剂，低于100 nM 时作用于大部分细胞系，抑制50% 生长(GI50)，作用于人无增殖细胞系具有有限的毒性。GSK461364抑制细胞周期进展是浓度依赖性的，高浓度时，使细胞在G2期发生延迟，较低浓度时使细胞停在M 期。目前, GSK461364按剂量递增方式首次用在人体试验阶段。携带TP53基因突变的细胞系对 GSK461364更敏感，且作用于一些p53野生型(WT)细胞，通过RNA沉默抑制p53 反应，使敏感性增加。而且, 这些更敏感的细胞系染色体不稳定性提高，这是与TP53突变相关的一个特点。[2] 在临床前期研究中, GSK461364作用于多种(>120)肿瘤细胞系，具有抗增殖活性，且有效抑制这些细胞系中的 83%和91%细胞增殖，IC50分别低于50和100 nM。[3] |
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|---|---|---|---|---|
| 激酶实验 | 酶实验 | |||
| 使用Z-Lyte 检测试剂盒(Ser/Thr肽 16)进行激酶反应，终实验体积为10 μL。反应含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 重组 Plk1 (H6-tev-PLK 1-603)。Plk1与0到1×103 nM GSK461364预温育60分钟。加入2 μM 肽，开始反应。在23oC下反应15分钟后, 反应淬火，根据Z′-Lyte建议发法处理，然后在EnVision酶标仪上读数。使用底物和产物标准，使原料荧光值转换为形成的产品浓度。随着与ATP竞争性抑制模式相一致的ATP浓度功能变化，则观察到GSK461364抑制效力发生变化，测定GSK461364作用的Ki最大上限值。 | ||||
| 细胞实验 | 细胞系 | 前列腺(LNCap,PC3),子宫(HeLa),胰脏(ASPC1),肉瘤(Saos-2)，卵巢(OVCAR8),胃(NCI-N87),黑色素瘤(SKMEL3,A431,MALME3M)，结肠(Colo205,SW620,HCT116),胸腺(SKBR3,MDA-MB-453,MCF7)，肺(NCI-H82,MV522,NCI-H522)等等癌细胞系 | ||
| 浓度 | 10 nM | |||
| 孵育时间 | 72小时 | |||
| 方法 | 癌细胞系接种在384孔板上。细胞在37oC下温育24小时。每孔加入GSK461364，浓度为10 nM。测定每组细胞系在T=0的实验值。72小时后,从残留细胞中抽提含GSK461364或DMSO的培养基，用4',6-二脒基-2-苯基吲哚进行核染色,使用 InCell1000 高通量分析仪测定荧光密度。在72小时时,计算每种浓度GSK461364在重复三次孔的每个孔中中，4',6-二脒基-2-苯基吲哚染色强度相对T=0时强度的百分数。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | p-Myt1 / Myt1 / Plk1 |
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26597303 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | GSK461364作用于培养细胞的生长，可以抑制细胞生长或产生细胞毒性，但在适当剂量处理下,可以导致移植瘤模型发生肿瘤衰退。GSK461364 作用于移植瘤模型，具有明显的抗癌活性。[1] GSK461364作用于小鼠移植瘤，使细胞周期停滞，这种作用存在剂量依赖性，与作用于肿瘤生长相关。[2] GSK461364腹腔注射处理不同移植瘤模型，包括Colo205移植瘤，导致衰退或肿瘤生长延迟。在体内，使用GSK461364抑制Plk1，导致有丝分裂停滞，形成由单极或倒塌的有丝分裂纺锤体组成的异常有丝分裂。[3] |
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|---|---|---|
| 动物实验 | Animal Models | 携带结肠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天进行。 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00536835 | Completed | Lymphoma Non-Hodgkin |
GlaxoSmithKline |
August 16 2007 | Phase 1 |
化学信息&溶解度
| 分子量 | 543.6 | 分子式 | C27H28F3N5O2S |
| CAS号 | 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 | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
Ethanol : 30 mg/mL (55.18 mM) DMSO : 10 mg/mL ( (18.39 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) 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:
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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