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CUDC-907

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Catalog No.
A4097
PI3K/HDAC抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,700.00
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5mg
¥ 1,630.00
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10mg
¥ 2,420.00
现货
50mg
¥ 6,180.00
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200mg
¥ 14,160.00
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Background

CUDC-907 is a dual-acting inhibitor of HDAC and PI3K with IC50 values of 1.7/5.0/1.8/2.8 nM (HDAC1/2/3/10) and 19/54/39 nM (PI3K).[1]

The phosphoinositide 3-kinases (PI3Ks) contain three classes of PI3K each with its own distinct lipid products and specific substrate. They are a family of lipid kinases that regulates a wide range of pathway by propagating intracellular signaling cascades. PI3K phosphorylates the 3’-OH group of phosphatidylinositols. This activated AKT, the protein Ser/Thr-kinase, by recruiting them to the cell membrane. The PI3K/AKT signaling pathway is critical in cancer, because it promotes cell growth and survival. The studies have proved that PI3K pathway plays an important role in cancer progression and treatment for lung cancers, breast cancer.[2, 3] Histone deacetylases (HDACs) and histone acetyltransferases (HATs) mediates the balance between histone deacetylation and acetylation. HDACs also regulate the acetylation status of signaling molecules, chaperones, and transcription factors that are non-histone proteins.[4]

CUDC-907 is a potent inhibitor of class I PI3K kinases and HDAC classes I and II enzymes. CUDC-907 resulted in increase of acetylated histones and non-histone proteins such as tubulin and p53. CUDC-907 also induced p21 protein in H460 cell lines. CUDC-907 dose-dependently decreases phosphorylation of AKT and its downstream targets, p70S6 and 4EBP-1 by inhibiting the PI3K pathway,, in H460 cells. CUDC-907 were able to inhibit the activation of MEK in cancer cell lines including NSCLC H460 cells, breast cancer BT-474 cells and NSCLC H1975 cells. CUDC-907 suppresses the RAF- MEK-MAPK signaling pathway through HDAC inhibition. CUDC-907 can also cause the decrease of both p-SRC) and p-SRC in RPMI-8226 multiple myeloma cells. CUDC-907 induced cell-cycle arrest at G2–M phase at the dose of 1 μM for 24h.[1]

CUDC-907 inhibited growth of the tumor in Daudi cancer cell xenografts dose-dependently. In a xenograft tumor model of DLBCL (SU-DHL4 diffuselarge B-cell lymphoma) CUDC-907 induced tumor regression after oral administration (100 mg/kg) or intravenous (50 mg/kg). CUDC-907 also caused tumor stasis in NSCLC cell xenografts [1].

References:
[1].  Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M et al: Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res 2012, 18(15):4104-4113.
[2].  Wong KK, Engelman JA, Cantley LC: Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 2010, 20(1):87-90.
[3].  Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009, 9(8):550-562.
[4].  Kim HJ, Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res 2011, 3(2):166-179.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt508.55
Cas No.1339928-25-4
FormulaC23H24N8O4S
Solubility≥25.45 mg/mL in DMSO, <2.5 mg/mL in EtOH, <2.34 mg/mL in H2O
Chemical NameN-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide
SDFDownload SDF
Canonical SMILESCN(CC1=CC2=C(S1)C(=NC(=N2)C3=CN=C(C=C3)OC)N4CCOCC4)C5=NC=C(C=N5)C(=O)NO
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

H460细胞

制备方法

在DMSO中的溶解度大于25.5 mg/mL。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

1 μM;16小时

实验结果

在H460细胞中,CUDC-907提升活化caspase-7、p21和c-PARP的水平。同时,CUDC-907降低BCL-2、BCL-xL和survivin的水平。

动物实验 [1]:

动物模型

Daudi NHL异种移植小鼠模型

给药剂量

25、50或100 mg/kg;口服给药

实验结果

在Daudi NHL异种移植小鼠模型中,CUDC-907呈剂量依赖性地抑制肿瘤生长。在100 mg/kg的剂量下,CUDC-907导致肿瘤停止生长,同时不会引起明显的毒性。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M et al: Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res 2012, 18(15):4104-4113.

生物活性

描述 CUDC-907是PI3K和HDAC的双重抑制剂,作用于PI3Kα、HDAC1、2、3 和10,IC50值分别为19 nM、1.7 nM、5 nM、1.8 nM和2.8 nM。
靶点 PI3Kα HDAC1 HDAC2 HDAC3 HDAC10  
IC50 19 nM 1.7 nM 5 nM 1.8 nM 2.8 nM  

质量控制

化学结构

CUDC-907