切换导航

CB-5083

现货
Catalog No.
B6032
p97抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,600.00
现货
5mg
¥ 1,200.00
现货
10mg
¥ 1,900.00
现货
50mg
¥ 4,000.00
现货
100mg
¥ 7,500.00
现货

电话: 021-55669583

邮箱: sales@apexbio.cn

全球经销商

Background

IC50: 15.4 nM

CB-5083 is an orally bioavailable inhibitor of p97. P97 is an AAA-ATPase involved in multiple cellular functions such as organelle membrane homotypic fusion and sorting of endosomal cargo. P97 is also known as valosin-containing protein which plays important roles in regulating protein homeostasis [1].

In vitro: CB-5083 is a selective potent inhibitor of p97’s second ATPase domain. CB-5083 might compete with ATP for the same binding site but may adopt a different orientation[2]. The IC50 of CB-5083 against wild-type (WT) p97 was 15.4 nM. CB-5083 could dose-dependently increase the cytosolic protein degradation in HEK293T, A549 and HCT116 cell lines [1]. CB-5083 treatment (2.5 μM) of A549 cells for 24h could induce cancer cell death [1].

In vivo: In female nude mice bearing HCT116, A549 lung carcinoma, and AMO-1 multiple myeloma xenograft tumors, oral administration of CB-5083 (100 mg/kg) for 6 h showed a significant antitumor response in tumors (TGI = 63%, p < 0.0001) [1,2].

Clinical trial: CB-5083 has entered phase 1 clinical trials in patients with multiple myeloma and solid tumors.

References:
Anderson D J, Le Moigne R, Djakovic S, et al.  Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis[J]. Cancer cell, 2015, 28(5): 653-665.
Zhou H J, Wang J, Yao B, et al.  Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)[J]. Journal of medicinal chemistry, 2015, 58(24): 9480-9497.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt413.47
Cas No.1542705-92-9
FormulaC24H23N5O2
Solubility≥20.65mg/mL in DMSO
Chemical Name(E)-1-(4-(benzylimino)-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbimidic acid
SDFDownload SDF
Canonical SMILESCC1=CC2=C(C(O)=N)C=CC=C2N1C3=NC4=C(/C(N3)=N\CC5=CC=CC=C5)COCC4
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

激酶实验 [1]:

结合实验

使用标准的基于NADH的偶联动力学ATP酶实验对CB-5083针对p97和突变体的IC50进行测定。该测定在50 μl体积的384孔板中进行,包含60 nM p97酶、500 μM ATP、3单位/ml丙酮酸激酶和乳酸脱氢酶、250 μM NADH和3.75 mM磷酸烯醇丙酮酸盐。在37℃孵育2小时后,于340 nM波长下测量ATP水解依赖性NADH的降低。在ATP浓度增加的NADH测定中测量了CB-5083的ATP竞争力。对于ADP-glo测定,将化合物稀释于DMSO中,进行三倍十点连续稀释以获得10 μM至0.16 nM的测定浓度。在37℃下将20 nM p97和20 μM ATP和连续稀释的化合物在5 μl体积中孵育15分钟进行测定。加入ADP glo试剂1和2。通过读取发光值并将其拟合为4点S形曲线来获得每种化合物的IC50。

细胞实验 [1]:

细胞系

稳定表达TCRα-GFP的HEK293T,A549和HCT116细胞系

溶解方法

该化合物在DMSO中的溶解度大于20.7 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

2.5 μM,6 hr

应用

在稳定表达TCRα-GFP的人类胚胎肾293T细胞中,CB-5083以剂量依赖性方式诱导TECα-GFP在ER中的积累,EC50为0.73 ± 0.04 μM。在肺癌细胞系A549中,CB-5083导致多泛素化蛋白质的积累。在HCT116细胞中,CB-5083导致较高分子量的K48泛素化蛋白质的积累。

动物实验 [2]:

动物模型

来自结肠直肠腺癌的HCT116、来自非小细胞肺癌的NCI-H1838、源自浆细胞瘤的AMO-1异种移植的裸鼠或SCID-Beige小鼠,和结肠直肠癌患者来源的异种移植(PDX)模型

给药剂量

口服,25和100 mg/kg,6 hr,每天口服管饲一次(qd)或两次(bid)连续4天,停药3天,即(qd4/3off)周期。

应用

口服CB-5083(25和100 mg/kg)诱导UPR和细胞凋亡。口服CB-5083抑制小鼠中人肿瘤异种移植物的生长。

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]. Anderson D J, Le Moigne R, Djakovic S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis[J]. Cancer Cell, 2015, 28(5): 653-665.

质量控制

化学结构

CB-5083