产品说明书

Defactinib

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Chemical Structure| 1073154-85-4 同义名 : VS-6063;PF-04554878
CAS号 : 1073154-85-4
货号 : A143423
分子式 : C20H21F3N8O3S
纯度 : 99%+
分子量 : 510.493
MDL号 : MFCD25977806
存储条件：

粉末 Keep in dark place,Inert atmosphere,Room temperature

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(97.94 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 6 mg/mL clear

PO 0.5% CMC-Na 45 mg/mL suspension

生物活性
靶点

  • FAK
描述 FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate the cytoskeleton and is reported to have increased expression in a number of tumor types, including breast, colon and ovarian cancers. Defactinib is a selective FAK inhibitor which dose-dependently down-regulated pFAK (Tyr397) at concentration ranging in 10nM-10μM in taxane-sensitive HeyA8 cells and 0.1-10μM in taxane-resistant HeyA8-MDR cells. Co-incubation of 1μM Defactinib and paclitaxel could decrease the paclitaxel-induced expression of YB-1 and its phosphorylation at Ser102 site, which has a potential role in oncogenic and drug-resistance pathways, as well as restored the location of YB-1 to cytoplasm, in HeyA8-MDR cells. For AKT is required to phosphorylation and translocation of YB-1, the signaling of AKT pathway was also examined. The resulted show that Defactinib could downregulate p-YB-1 and its nuclear translocation in an AKT-dependent manner, as well as inhibit p-FAK-Y397 and p-AKT-S473 in taxane-resistant SKOV3 cells. This inhibition of YB-1 by Defactinib through FAK may downregulate the expression of CD44, a downstream target of YB-1 and a partial contributor to the PTX-resistant phenotype, in HeyA8-MDR cells. Combined therapy of paclitaxel with Defactinib >25 mg/kg orally twice a day resulted in greater reduction in tumor growth of PTX-resistant models, including HeyA8-MDR and SKOV3-TR xenografts[1].
作用机制 Defactinib is an ATP-competitive, reversible inhibitor of FAK.[2]
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.96mL

0.39mL

0.20mL

9.79mL

1.96mL

0.98mL

19.59mL

3.92mL

1.96mL
参考文献

[1]Kang Y, Hu W, et al. Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst. 2013 Oct 2;105(19):1485-95.

[2]Shimizu T, Fukuoka K, et al. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016 May;77(5):997-1003.

[3]Kolev VN, Tam WF, et al. Inhibition of FAK kinase activity preferentially targets cancer stem cells. Oncotarget. 2017;8(31):51733-51747.