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(S)-Crizotinib

现货
Catalog No.
A8802
MTH1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,100.00
现货
5mg
¥ 750.00
现货
50mg
¥ 4,200.00
现货

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Background

(S)-crizotinibthe selectively inhibited MTH1 catalytic activity with IC50 of 72 nM, while clinically used (R)-enantiomer of the drug was inactive with IC50 of 1375 nM. Furthermore, direct-binding assays (ITC) indicated a 16-fold higher affinity of the (S)-enantiomer towards MTH1 compared with (R)-enantiomer. By using Km concentrations of substrates, the average IC50 values for (S)-crizotinib and the MTH1 substrates 8-oxo-dGTP and 2-OH-dATP were 330 nM and 408 nM respectively. (S)-crizotinib efficiently inhibited colony formation of SW480 cells andKRAS-mutated PANC1 cells, similar to SCH51344. In addition, in vitro Kd measurements indicated that (S)-crizotinib was considerably less potent than the (R)-enantiomer against the established targets ALK,MET and ROS1. (S)-crizotinib did not lead to the detection of any significant effects on proliferation in SW480 cells and showed highest toxicity towards the SV40T and KRASV12 cells. (S)-crizotinib, in contrast to (R)-crizotinib, efficiently stabilized MTH1 validating the differential targeting within BJ-KRASV12 cells using a cellular thermal shift assay. (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models as a result of disruption of nucleotide pool homeostasis via MTH1 inhibition.

In vivo mouse xenograft studies showed (S)-crizotinib, but not the (R)-enantiomer, was able to impair overall tumour progression aswell as specifically reduce tumour volume by more than 50%.

References:
1. Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. NATURE,2014;508:222-227

文献引用

1. Qing X, Shao Z, et al. "Anticancer effect of (S)-crizotinib on osteosarcoma cells by targeting MTH1 and activating reactive oxygen species." Anticancer Drugs. 2018 Apr;29(4):341-352. PMID:29420337
2. Stewart E, Federico SM, et al. "Orthotopic patient-derived xenografts of paediatric solid tumours." Nature. 2017 Sep 7;549(7670):96-100. PMID:28854174
3. Kawamura T, Kawatani M, et al. "Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival." Sci Rep. 2016 May 23;6:26521. PMID:27210421
4. J Adachi, et al. "Proteome-wide discovery of unknown ATP-binding proteins and kinase inhibitor target proteins using an ATP probe." J Proteome Res. 2014 Sep 17. PMID:25230287

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt450.34
Cas No.877399-52-5;1374356-45-2
FormulaC21H22Cl2FN5O
Solubility≥33.3mg/mL in DMSO
Chemical Name3-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
SDFDownload SDF
Canonical SMILESCC(C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N
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

细胞实验[1]:

细胞系

BJ、H1437、H2122、H23、H358、H460、HCT116和U2OS细胞

溶解方法

在DMSO中的溶解度>10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

BJ、SV40T、RASV12细胞(5 μM,3 h);U2OS细胞(5 μM,24 h)

应用

(S)-crizotinib选择性地抑制MTH1的催化活性,IC50值为72 nM,而临床上使用的R异构体是无效的,IC50值为1375 nM。此外,直接结合实验(ITC)表明,与R异构体相比,(S)-crizotinib对MTH1有16倍更高的亲和力。通过测定底物的Km浓度,(S)-crizotinib和MTH1的底物8-oxo-dGTP / 2-OH-dATP的平均IC50值分别为330 nM和408 nM。(S)-crizotinib有效抑制SW480细胞和KRAS突变的PANC1细胞的集落形成,与SCH51344效果相似。此外,体外Kd测量表明,(S)-crizotinib对既定靶点ALK、MET和ROS1的效果不如(R)-crizotinib。(S)-crizotinib对SW480细胞的增殖没有显著影响,而对SV40T和KRASV12细胞具有最大的细胞毒性。在人结肠癌细胞中,(S)-crizotinib诱导DNA单链断裂的增加,激活DNA修复。在动物模型中,(S)-crizotinib通过抑制MTH1,扰乱核苷酸池的动态平衡,从而有效抑制肿瘤生长。

动物实验[1]:

动物模型

SCID小鼠(雌性,5-6周龄)

剂量

25 mg/kg/day,皮下注射;50 mg/kg/day,口服给药

应用

体内小鼠异种移植研究表明,(S)-crizotinib,而非其R异构体,能够损害整体肿瘤进展,特异性减少超过50%的肿瘤体积。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

1. Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. NATURE,2014;508:222-227

生物活性

描述 (S)-Crizotinib,crizotinib的(S)型异构体,是一种有效的MTH1(NUDT1)抑制剂,非细胞试验中IC50值为72 nM。
靶点 MTH1          
IC50 72 nM          

质量控制

化学结构

(S)-Crizotinib

相关生物数据

(S)-Crizotinib

相关生物数据

(S)-Crizotinib

相关生物数据

(S)-Crizotinib