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LY2603618

现货
Catalog No.
A8638
Chk1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,300.00
现货
5mg
¥ 900.00
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10mg
¥ 1,400.00
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50mg
¥ 4,400.00
现货
200mg
¥ 10,000.00
现货

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Background

LY2603618 is a novel small molecular checkpoint kinase 1 (Chk1) inhibitor that has direct anti-tumour effect [1], as well as desensitizing tumour cell against DNA-damaging chemotherapy treatment [2].

Checkpoint kinase 1 (Chk1) is a type of kinase that coordinates damaged-DNA repair [1]. Some tumour cells have been found to possess over-regulated populations of Chk1 that desensitize the cell from DNA-targeting chemotherapy, promoting tumour proliferation [3].

LY2603618 inhibits Chk1 by competing with ATP molecules [2]. In A549 and H1299 non-small cancer cell lines, lethal concentration of LY2603618 (10 µM) not only resulted in cell proliferation arrest (increase population of cell at G2/M phase from 13% to 38%) but also directly DNA damage, the latter of which was indicated by the increasing occurrence of H2AX phosphorylation[1].

In vivo, experiment was carried out to determine the combining effect of LY2603618 with other chemotherapy[2] . In mice xenograft model that inculated with Calu-6 lung cancer cell, combining administration of injected gemcitabine 150 mg/kg and orally uptake LY2603618 (200 mg/kg) resulted in increased DNA damage of tumour, as was demonstrated by a 2-fold increase in Chk1 s345 phosphorylation in comparison with mice treated with gemcitabine alone[2].

References:
[1].  Wang F Z, Fei H R, Cui, Y J et al. The checkpoint 1 kinase inhibitor LY2603618 induces cell cycle arrest, DNA damage response and autophagy in cancer cells. Apoptosis, 2014,19:1389-1398.
[2].  King C, Diaz H, Barnard D et al.Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs, 2014, 32: 213-26.
[3].  Zhang Y. & Hunter T. Roles of Chk1 in cell biology and cancer therapy. Int J Cancer, 2014. 134: 1013-23.

文献引用

1. Yang X, Pan Y, et al. "RNF126 as a biomarker of a poor prognosis in invasive breast cancer and CHK1 inhibitor efficacy in breast cancer cells." Clin Cancer Res. 2018 Jan 11. pii: clincanres.2242.2017. PMID:29326282
2. Höhn A, Krüger K, et al. "Distinct mechanisms contribute to acquired cisplatin resistance of urothelial carcinoma cells." Oncotarget. 2016 Jul 5;7(27):41320-41335. PMID:27191498
3. Zhang Y, Lai J, et al. "Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress." Oncotarget. 2016 Jun 7;7(23):34688-702. PMID:27167194

Chemical Properties

StorageStore at -20°C
M.Wt436.3
Cas No.911222-45-2
FormulaC18H22BrN5O3
Solubility≥43.6mg/mL in DMSO with gentle warming
Chemical Name1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea
SDFDownload SDF
Canonical SMILESCC1=CC(=C(C=C1Br)NC(=O)NC2=NC=C(N=C2)C)OCC3CNCCO3
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

HeLa宫颈癌细胞,Calu-6非小细胞肺癌细胞,HT29和HCT-116结肠癌细胞

溶解方法

该化合物在DMSO中的溶解度大于21.8 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

1250 nM,2500 nM,24 h

应用

LY2603618 (1250 nM)明显减少G1群体细胞数目,增加晚S期细胞数目。LY2603618(5000 nM)导致细胞处于S期,DNA含量介于2和4N之间。LY2603618诱导DNA损伤并阻止DNA合成,同时增加表达有丝分裂早期标志物的细胞数量。LY2603618导致细胞缺乏正常的有丝分裂。 LY2603618使pH3(S10)染色细胞的比例增加,相比于对照细胞,诱导异常前中期阻滞。LY2603618增加gemcitabine在p53突变体HT-29细胞中的效力,但不增加其在野生型p53 HCT-116细胞中的功效。

动物实验 [1]:

动物模型

携带Calu-6异种移植物的雌性Harlan无胸腺裸鼠

给药剂量

口服,200 mg/kg

应用

在Calu-6肿瘤异种移植模型中,LY2603618有效抑制gemcitabine激活的Chk1,而对ATR的激活没有影响。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. King C, Diaz H, Barnard D, et al. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor[J]. Investigational new drugs, 2014, 32(2): 213-226.

生物活性

Description LY2603618 is a selective inhibitor of Chk1 with potential anti-tumor activity.
Targets Chk1          
IC50            

质量控制

化学结构

LY2603618

相关生物数据

LY2603618

相关生物数据

LY2603618

相关生物数据

LY2603618