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CH5183284 (Debio-1347)

现货
Catalog No.
B4985
口服FGFR抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,210.00
现货
5mg
¥ 1,030.00
现货
25mg
¥ 3,340.00
现货
100mg
¥ 6,980.00
Ship with 10-15 days

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Background

CH5183284 (Debio-1347) is a selective and novel inhibitor of FGFR with IC50 value of 9.3, 7.6, 22 and 290 nM for FGFR1, FGFR2, FGFR3 and FGFR4, respectively [1].

Fibroblast growth factor receptors (FGFRs) are tyrosine kinases and receptors for fibroblast growth factors and consist of FGFR1, FGFR2, FGFR3 and FGFR4. In cancer, FGFR is activated by point mutations, gene amplification or chromosomal translocations/rearrangements and is involved in angiogenesis, cell growth, cell migration, invasion and metastasis [1].

CH5183284 (Debio-1347) is a selective and novel FGFR inhibitor. In a competitive binding assay, CH5183284 (Debio-1347) binding with FGFR1, FGFR2, FGFR3, FGFR4 and KDR with Kd values of 20, 20, 25, 740 and 960 nM, respectively. In DMS114, SNU-16 and KMS11 cell lines, CH5183284 (Debio-1347) (100-300 nM) inhibited autophosphorylation of FGFR1, FGFR2 and FGFR3. In cancer cell lines with the FGFR genetic alterations, CH5183284 (Debio-1347) showed antiproliferative activity [1].

In xenograft mouse models, CH5183284 (Debio-1347) inhibited tumor growth against xenografts with FGFR genetic alterations such as KG1 (leukemia, FGFR1OP-FGFR1 fusion), MFE-280 (endometrial cancer, FGFR2 S252W mutation), SNU-16 (gastric cancer, FGFR2 amplification), RT112/84 (bladder cancer, FGFR3-TACC3 fusion) and UM-UC-14 (bladder cancer, FGFR3 S249C mutation) by 134%, 100%, 147%, 125% and 116%, respectively [1].

Reference:
[1].  Nakanishi Y, Akiyama N, Tsukaguchi T, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther, 2014, 13(11): 2547-2558.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt356.38
Cas No.1265229-25-1
FormulaC20H16N6O
Solubility≥35.6mg/mL in DMSO
SDFDownload SDF
Canonical SMILESCC1=NC(C=C2)=C(N1)C=C2N3N=CC(C(C(N4)=CC5=C4C=CC=C5)=O)=C3N
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]:

蛋白激酶试验

采用放射性滤波器试验,使用微板闪烁计数器测定33Pi整合,以评估CH5183284/Debio 1347对FGFR1的抑制作用。根据标准方法,使用LANCE Eu-W1024标记的抗磷酸酪氨酸PT66抗体进行均相时间分辨荧光试验,测定LCK、EGFR、KIT、MET、SRC、BRK、FGFR2、Flt3、LTK、INSR、YES、ABL、EPHA2、ZAP70、Fyn、IGF1R、KDR和PDGFR对底物多肽的磷酸化活性。使用EnVision HTS酶标仪测定时间分辨荧光。通过IMAP FP Screening Express Progressive Binding System测定Aurora A、Akt1/PKBα、PKA、Cdk1/cyclin B、Cdk2/cyclin A、PKCα、PKCβ1和PKCβ2对底物多肽的活性。使用EnVision HTS酶标仪测定荧光偏振。

细胞实验 [1]:

细胞系

327种人类肿瘤细胞系

制备方法

在DMSO中的溶解度大于17.8 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

0.076 ~ 10,000 nM;4天

实验结果

在DMS114(FGFR1 扩增),SNU-16(FGFR2扩增)和KMS11[t(4;14) 易位和FGFR3 Y373C突变]细胞中,100 ~ 300 nM CH5183284抑制FGFR1、FGFR2和FGFR3的自磷酸化。因此,CH5183284选择性地抑制含FGFR突变的癌细胞系的增殖活性。此外,CH5183284对含FGFR2的V564F癌细胞突变株(对其它FGFR抑制剂具有耐药性)也显示出抑制作用。

动物实验 [1]:

动物模型

携带KG1、MFE280、SNU-16、RT112/84或UM-UC-14异种移植瘤的小鼠

给药剂量

100 mg/kg/day;口服给药

实验结果

CH5183284选择性地显著抑制携带FGFR突变的各种异种移植瘤,例如KG1(白血病,FGFR1OP-FGFR1融合),MFE-280(子宫内膜癌,FGFR2 S252W突变),SNU-16(胃癌,FGFR2扩增),RT112/84(膀胱癌,FGFR3-TACC3融合)以及UM-UC-14(膀胱癌,FGFR3 S249C突变)。

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]. Nakanishi Y, Akiyama N, Tsukaguchi T, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther, 2014, 13(11): 2547-2558.

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