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RO4929097

现货
Catalog No.
A4005
γ-secretase抑制剂
组合的产品项目
规格价格库存 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
Ship with 10-15 days

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Background

RO4929097 is a small-molecule inhibitor of γ secretase with IC50 of 4 nM and EC50 of 5 nM [1]. It shows no in vitro inhibitory activity on the closely related proteases. It also has greater than 100-fold selectivity with respect to 75 other proteins of various types [1]. RO4929097 binds to γ secretase and inhibits its protease activity, therefore blocking the cleavage of Notch and reducing Notch signaling. Up-regulaton of this signaling pathway promotes tumorigenesis of multiple cancers.

RO4929097 has shown potential antitumor activity both in vitro and in vivo. It impaired the growth of melanoma cell lines and tumor formation of human primary melanoma xenograft [2]. It slowed proliferation and reduces colony formation of breast cancer cell lines[1]. In addition, RO4929097 decreased tumor formation in xenograft models of colorectal, pancreatic, lung cancer and melanoma[1, 2]. RO4929097 has been tested in multiple phase I/II clinical trials in patients with advanced solid tumors, either as monotherapy or in combination with other anti-tumor agents[3-8].

References:
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.

文献引用

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

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt469.4
Cas No.847925-91-1
FormulaC22H20F5N3O3
Solubility≥23.47 mg/mL in DMSO, ≥45.2 mg/mL in EtOH with ultrasonic, <2.41 mg/mL in H2O
Chemical Name2,2-dimethyl-N-[(7S)-6-oxo-5,7-dihydrobenzo[d][1]benzazepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)propanediamide
SDFDownload SDF
Canonical SMILESCC(C)(C(=O)NCC(C(F)(F)F)(F)F)C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3NC1=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

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.

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      

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