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CCT251545

现货
Catalog No.
B5979
WNT信号的具有口服生物利用度的有效抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,950.00
现货
10mg
¥ 3,250.00
现货
20mg
¥ 4,550.00
现货
50mg
¥ 8,450.00
现货

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Background

CCT251545 is an orally bioavailable and potent inhibitor of WNT signaling with IC50 value of 5 nM [1].

The WNT signaling network controls cellular functions such as proliferation and differentiation, and is a major regulator of mammalian development. WNT signaling is frequently deregulated in malignancy, especially in colon cancer, and plays an important role in the generation and maintenance of cancer stem cells [1].

CCT251545 is an orally bioavailable and potent WNT signaling inhibitor discovered through high-throughput cell-based screening. CCT251545 is also a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 changed gene expression regulated by WNT pathway and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1 [2]. CCT251545 also inhibited GSK3α and -β with IC50 values of 0.462 and 0.690 μM. In APC mutant human colorectal cancer cell line (COLO205-F1756 clone 4), CCT251545 inhibited WNT pathway activity with IC50 value of 0.035 nM [1].

In both mouse and rat, CCT251545 exhibited moderate clearance with moderate to high oral bioavailability. In mice bearing COLO205-F1756 clone 4 tumor xenografts, CCT251545 (70 mg/kg po bid for 9 days) significantly inhibited WNT signaling and reduced tumor weights by 37.5% [1].

References:
[1].  Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem, 2015, 58(4): 1717-1735.
[2].  Dale T, Clarke PA, Esdar C, et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol, 2015, 11(12): 973-980.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt421.92
Cas No.1661839-45-7
FormulaC23H24ClN5O
Solubility≥42.2mg/mL in DMSO
Chemical Name8-(3-chloro-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one
SDFDownload SDF
Canonical SMILESO=C(NCC1)C1(CC2)CCN2C3=C(C4=CC=C(C5=CN(C)N=C5)C=C4)C=NC=C3Cl
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

APC突变人结肠直肠癌细胞系(COLO205-F1756克隆体4)

制备方法

该化合物可溶于DMSO。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

0.035 μM

实验结果

在COLO205-F1756克隆体4中,CCT251545有效抑制WNT信号通路活性,其IC50值为0.035 μM。此外,CCT251545不影响内源TCF1或TCF4水平。

动物实验 [1]:

动物模型

携带COLO205-F1756克隆体4异种移植瘤的小鼠

给药剂量

70 mg/kg;口服给药;每天2次,持续9天

实验结果

在携带COLO205-F1756克隆体4异种移植瘤的小鼠中,CCT251545(70 mg/kg;口服给药;每天2次,持续9天)显著抑制WNT信号传导,并使肿瘤重量减少了37.5%。

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]. Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem, 2015, 58(4): 1717-1735.

质量控制

化学结构

CCT251545