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RO4929097γ-secretase抑制剂

RO4929097

产品编号:A4005
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规格 单价 库存 订购数量
10mM (in 1mL DMSO) ¥1,200.00 现货
5mg ¥1,100.00 现货
10mg ¥2,000.00 现货
50mg ¥5,900.00 现货
200mg ¥14,900.00 10-15 工作日发货

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Sample solution is provided at 25 µL, 10mM.

引用文献

1. Frank SB, Berger PL, et al. "Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC." J Cell Sci. 2017 Jun 1;130(11):1952-1964. PMID:28446540

质量控制

化学结构

RO4929097

相关生物数据

RO4929097
RO4929097 inhibits cell proliferation. The indicated cell lines were treated with DMSO (white circles) or 10 μM RO4929097 (black circles). A representative curve of three independent experiments is reported. ***p<0.001.

相关生物数据

RO4929097

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化学性质

CAS号 847925-91-1 SDF Download SDF
化学名 2,2-dimethyl-N-[(7S)-6-oxo-5,7-dihydrobenzo[d][1]benzazepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)propanediamide
SMILES CC(C)(C(=O)NCC(C(F)(F)F)(F)F)C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3NC1=O
分子式 C22H20F5N3O3 分子量 469.4
溶解度 ≥23.47 mg/mL in DMSO, ≥45.2 mg/mL in EtOH with ultrasonic, <2.41 mg/mL in H2O 储存条件 Store at -20°C
物理性状 A solid 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

描述 RO4929097是一种γ-secretase抑制剂,IC50值为4 nM,抑制Aβ40和Notch的细胞内加工,EC50值分别为14 nM和5 nM。
靶点 γ secretase Aβ40 ICN      
IC50 4 nM 14 nM 5 nM      

实验操作

细胞实验[1]:

细胞系

SUM190和SUM149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

1 μM,2D培养:14天;3D培养:7天

应用

在RO4929097存在或缺乏时,用逐渐增加剂量的电离辐射处理,2D菌落生长10-14天,而微球体生长1周。在1 μM浓度时,RO4929097能够增加粘附细胞对辐射的敏感性,在SUM190细胞比SUM149细胞中具有更显著的效应。在高剂量电离辐射下有利于癌症干细胞富集的条件下,同等剂量的RO4929097有助于细胞生长。2D和3D培养之间的差异表明,Notch抑制剂的显著效果可能需要细胞接触。

动物实验[2]:

动物模型

植入WM3248细胞的NOD/SCID/IL2gammaR-/- (NOG)小鼠

剂量

10 mg/kg/day,30天;口服给药

应用

RO4929097减少肿瘤生长,对提取的肿瘤进行重量评估时其效果更加明显。与对照相比,RO4929097处理的肿瘤具有更低水平的黑色素瘤干细胞标记CD166、CD271 和JARID1B的表达。

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] Debeb B G, Cohen E N, Boley K, et al. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast cancer research and treatment, 2012, 134(2): 495-510.

[2] Huynh C, Poliseno L, Segura M F, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PloS one, 2011, 6(9): e25264.

研究更新

1. A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br J Cancer. 2013 Aug 20;109(4):943-9. doi: 10.1038/bjc.2013.380. Epub 2013 Jul 18.
Abstract
The development of the combination therapy of RO4949097 and cediranib is based on the understanding of the Notch signaling’s role in tumorigenesis and drug resistance.
3. Implications of plasma protein binding for pharmacokinetics and pharmacodynamics of the γ-secretase inhibitor RO4929097. Clin Cancer Res. 2012 Apr 1;18(7):2066-79. doi: 10.1158/1078-0432.CCR-11-2684. Epub 2012 Feb 20.
Abstract
The RO4929097 binding in plasma and its potential impact on the pharmacokinetics and pharmacodynamics of RO4929097 were investigated.
4. PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor. Anticancer Res. 2013 Apr;33(4):1307-16.
Abstract
The anti-melanoma activity of RO4929097, a GSI catalyzing the cleavage of the Notch receptor, is associated with PTEN expression, where RO4929097 alone or in combination with chemotherapy induces apoptosis through reducing AKT phosphorylation in melanoma cells expressing PTEN.
5. A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer. 2012 May;48(7):997-1003. doi: 10.1016/j.ejca.2012.02.056. Epub 2012 Mar 23.
Abstract
RO4929097, a γ-secretase inhibitor was assessed for its activity in patients with metastatic, refractory colorectal cancer.

产品描述

RO4929097是γ分泌酶(γ-secretase)的小分子抑制剂,IC50和EC50值分别为4 nM和5 nM,对密切相关的蛋白酶没有体外抑制活性。相对于75种其它各种类型的蛋白酶,RO4929097对γ分泌酶具有大于100倍的选择性[1]。RO4929097与γ分泌酶结合,抑制其蛋白酶活性,从而阻断Notch的切割,减少Notch信号。Notch信号通路的上调促进多种肿瘤的发生。

据报道,RO4929097在体外和体内均具有潜在的抗肿瘤活性。RO4929097抑制黑色素瘤细胞的生长和人原发性黑色素瘤异种移植物的肿瘤形成[2]。在乳腺癌细胞中,RO4929097减慢细胞增殖,减少集落形成[1]。此外,在结直肠癌、胰腺癌、肺癌和黑色素瘤异种移植模型中,RO4929097抑制肿瘤形成[1, 2]。在多个I / II期临床试验中,RO4929097单独给药或与其它抗癌剂联合给药用于治疗晚期实体瘤患者[3-8]。

参考文献:
1. Luistro L, He W, Smith M et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009; 69: 7672-7680.
2. Huynh C, Poliseno L, Segura MF et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 2011; 6: e25264.
3. Richter S, Bedard PL, Chen EX et al. A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). Invest New Drugs 2014; 32: 243-249.
4. Sahebjam S, Bedard PL, Castonguay V et al. A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br J Cancer 2013; 109: 943-949.
5. Diaz-Padilla I, Hirte H, Oza AM et al. A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest New Drugs 2013; 31: 1182-1191.
6. Tolcher AW, Messersmith WA, Mikulski SM et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 2012; 30: 2348-2353.
7. Strosberg JR, Yeatman T, Weber J et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer 2012; 48: 997-1003.
8. Kolb EA, Gorlick R, Keir ST et al. Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a gamma-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer 2012; 58: 815-818.