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MK-1775

现货
Catalog No.
A5755
Wee1激酶抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
5mg
¥ 850.00
现货
10mg
¥ 1,300.00
现货
50mg
¥ 3,950.00
现货
100mg
¥ 6,600.00
现货

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Background

MK-1775 is a potent and selective Wee1 inhibitor with an IC50 of 5.2 nM in a cell-free assay. MK-1775 abolishes cyclin-dependent kinase 1 (CDC2) activity by phosphorylation of the Tyr15 residue [1]. Wee1 is a nuclearkinasebelonging to theSer/Thr familyof protein kinases. Wee1 kinase negatively regulates entry into mitosis by catalyzing the inhibitory tyrosine phosphorylation of CDC2/cyclin B kinase. Dysfunction of Wee1 will produce smaller than normal daughter cell [2].

In vitro:MK-1775 dose-dependently inhibited phosphorylation of CDC2 at tyr15 and abrogated the G2DNA damage checkpoint. MK-1775 inhibited Wee1 kinase in an ATP-competitive manner with an IC50 value of 5.2 nmol/L in the in vitro kinase assays. Compared to Wee1, MK-1775 displayed 2- to 3-fold less potency against Yes with the IC50value of 14 nM, 10-fold less potency against seven other kinases with >80% inhibition at 1 μM, and >100-fold selectivity over human Myt 1, another kinase that inhibited cyclin-dependent kinase 1 (CDC2) by phosphorylation at an alternative site (Thr14). By abrogating the DNA damage checkpoint via blockade of Wee1 activity in WiDr cells bearing mutated p53, MK-1775 treatment inhibited the basal phosphorylation of CDC2 at Tyr15 (CDC2Y15) with an EC50 of 49 nM, and dose-dependently suppressed gemcitabine-, carboplatin- or cisplatin-induced phosphorylation of CDC2 and cell cycle arrest, with the EC50 of 82 nM and 81 nM, 180 nM and 163 nM, as well as 159 nM and 160 nM, respectively. In WiDr and H1299 cells, MK-1775 treatment (30-100 nM)showed no significant antiproliferative effects, whereas MK-1775 at 300 nM was sufficient to inhibit Wee1 by >80%, displayed moderate but significant antiproliferative effects by 34.1% in WiDr cells and 28.4% in H1299 cells [1].

References:
[1].  Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents[J]. Molecular cancer therapeutics, 2009, 8(11): 2992-3000.
[2].  McGowan C H, Russell P. Cell cycle regulation of human WEE1[J]. The EMBO journal, 1995, 14(10): 2166.

文献引用

1. Yuan ML, Li P, et al. "Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma." Front Pharmacol. 2018 Sep 28;9:1041. PMID:30323762
2. Liu JC, Granieri L, et al. "Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer." Cell Rep. 2018 Apr 3;23(1):112-126. PMID:29617654

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt500.6
Cas No.955365-80-7
FormulaC27H32N8O2
SynonymsMK1775,MK 1775
Solubility≥25.03mg/mL in DMSO, <2.95 mg/mL in EtOH, <2.52 mg/mL in H2O
Chemical Name1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one
SDFDownload SDF
Canonical SMILESCC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

体外激酶试验

使用重组人Wee1。使用10 μM ATP,1.0 μCi [γ-33P]ATP和2.5 μg poly(Lys, Tyr)作为底物,加入不同浓度的MK-1775,激酶反应在30 ℃下进行30分钟。在MultiScreen-PH平板上显示整合到底物中的放射性,使用液体闪烁计数器进行定量分析。

细胞实验 [1]:

细胞系

WiDr和H1299细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

30、100或300 nM;24小时

实验结果

同时给予30 nM和100 nM MK-1775使Gemcitabine的IC50值降至21.5 nM和7.1 nM。在另一种p53缺失的肺癌细胞系 (H1299) 中,也可以观察到MK-1775稍微增强Gemcitabine的作用。

动物实验 [1]:

动物模型

携带WiDr、HeLa-luc或TOV21G-shp53肿瘤的裸大鼠模型

给药剂量

20或30 mg/kg;口服给药

实验结果

在携带WiDr肿瘤的大鼠中,单独给予20 mg/kg MK-1775显示出微小的抗肿瘤作用。在给药后第3天,其T/C值达69%。在携带HeLa-luc或TOV21G-shp53肿瘤的大鼠中,MK-1775也显示出适度的抗肿瘤作用。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Hirai H, Iwasawa Y, Okada M et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009 Nov;8(11):2992-3000.

生物活性

Description MK-1775 is a potent and selective inhibitor of Wee1 with IC50 of 5.2 nM.
Targets Wee1          
IC50 5.2 nM          

质量控制

化学结构

MK-1775

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MK-1775

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