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MK-0752γ-分泌酶抑制剂

MK-0752

产品编号:A4006
ApexBio 的所有产品仅用作科研,我们不为任何个人用途提供产品和服务
规格 单价 库存 订购数量
10mM (in 1mL DMSO) ¥2,200.00 现货
5mg ¥1,700.00 现货
10mg ¥2,300.00 现货
50mg ¥5,900.00 现货
100mg ¥10,800.00 现货

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Sample solution is provided at 25 µL, 10mM.

引用文献

1. Chen X, Gong L, et al. "Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752." Gynecol Oncol. 2016 Mar;140(3):537-44. PMID:26704638

质量控制

化学结构

MK-0752

相关生物数据

MK-0752

相关生物数据

MK-0752

相关生物数据

MK-0752

MK-0752 Dilution Calculator

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MK-0752 Molarity Calculator

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化学性质

CAS号 471905-41-6 SDF Download SDF
别名 MK 0752, MK0752
化学名 3-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid
SMILES C1CC(CCC1CCC(=O)O)(C2=C(C=CC(=C2)F)F)S(=O)(=O)C3=CC=C(C=C3)Cl
分子式 C21H21ClF2O4S 分子量 442.9
溶解度 ≥22.15 mg/mL in DMSO, ≥48.8 mg/mL in EtOH with ultrasonic, <2.46 mg/mL in H2O 储存条件 Store at -20°C
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。

生物活性

Targets γ-secretase          
IC50 5 nM          

实验操作

细胞实验[1]:

细胞系

SH-SY5Y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

IC50:5 nM

应用

MK-0752是一种适度有效的γ分泌酶抑制剂。在人SH-SY5Y细胞中,MK-0752剂量依赖地抑制Aβ40的产生,IC50值为5 nM。

动物实验[1]:

动物模型

雄性CMP恒河猴

剂量

60 mg/kg和240 mg/kg;口服给药。

应用

MK-0752口服给药后剂量依赖地减少Aβ的水平。240 mg/kg的MK-0752处理48小时后,Aβ的水平仅恢复到基线水平的50%,而60 mg/kg治疗组在30小时之后Aβ的水平恢复到基线水平,而在治疗后的33-48小时,血浆Aβ水平出现反弹,高于基线水平。

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] Cook J J, Wildsmith K R, Gilberto D B, et al. Acute γ-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-β production to alternative APP fragments without amyloid-β rebound[J]. The Journal of Neuroscience, 2010, 30(19): 6743-6750.

研究更新

1. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol. 2012 Jul 1;30(19):2307-13. doi: 10.1200/JCO.2011.39.1540. Epub 2012 Apr 30.
Abstract
MK-0752, an inhibitor of γ-secretase, has been assessed for safety, maximum-tolerated dose, PKs, pharmacodynamics and antitumor efficacy in a phase I study.
2. Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Clin Oncol. 2011 Sep 10;29(26):3529-34. doi: 10.1200/JCO.2011.35.7806. Epub 2011 Aug 8.
Abstract
The MTD, DLTs and pharmacokinetic properties of MK-0752, a γ-secretase inhibitor, have been evaluated in children with refractory or recurrent CNS malignancies.
4. Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52. doi: 10.1016/j.jchromb.2010.07.019. Epub 2010 Jul 30.
Abstract
The concentration of MK-0752, a γ-secretase inhibitor, in human plasma can be determined by the HTLC-ESI-MS/MS method, which was used to measure plasma MK-0752 levels in a Phase I study of pediatric patients with recurrent or refractory brain tumors.

产品描述

MK-0752是一种在临床开发上非常有效的γ分泌酶抑制剂,IC50值约为50 nM。γ分泌酶是Notch切割机制的重要组成部分,它可以催化受体蛋白跨膜结构域的切割。

Notch信号需要γ分泌酶来切割Notch,释放Notch的胞内结构域(NICD)从而激活靶基因的转录。Notch信号在正常组织发育、细胞命运决定、增殖和存活中起着重要作用。通过结合同源配体Delta1、Delta2、Delta3、Jagged1和Jagged2,Notch信号被激活。在体外,抑制Notch信号可以抑制BC细胞的增值。

参考文献:
I.  E. Krop, M. Kosh, I. Fearen, J. Savoie, A. Dallob, C. Matthews, J. Stone, E. Winer, S. J. Freedman and P. Lorusso. Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. J Clin Oncol (Meeting Abstracts) June 2006 vol. 24 no. 18_suppl 10574.
Maryam Fouladi, Clinton F.  Stewart, James Olson, Lars M. Wagner, Arzu Onar-Thomas, Mehmet Kocak, Roger J. Packer, Stewart Goldman, Sridharan Gururangan, Amar Gajjar, Tim Demuth, Larry E. Kun, James M. Boyett and Richard J. Gilbertson. Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study. JCO September 10, 2011 vol. 29 no. 26 3529-3534