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PF-06463922

现货
Catalog No.
B4882
ALK/ROS1的强效选择性抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 830.00
现货
5mg
¥ 650.00
现货
25mg
¥ 2,400.00
Ship with 10-15 days

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Background

PF-06463922 is a potent and selective ALK/ROS1 inhibitor with IC50 values ranging from 0.19-0.53 nM for the kinase activity of ROS1 fusion enzymes [1].

The receptor tyrosine kinase c-ros oncogene1 (ROS1) is a receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families [1].

Via cellular ROS1 autophosphorylation in the recombinant enzyme assay, PF-06463922 showed a 30-fold improved potency against ROS1, compared with crizotinib, ceritinib, alectinib and foretinib (XL-880). Engineered NIH 3T3 cells were expressing oncogenic human ROS1 fusions. In these cells, PF-06463922 was more potent than foretinib and crizotinib by >10 folds, more potent than alectinib and ceritinib by >100 folds against cellular ROS1 autophosphorylation [1].

Oncogenic gene fusions involving the 3' region of ROS1 kinase had been found in various human cancers [2]. Mice bearing CD74-ROS1, CD74-ROS1G2032R and FIG-ROS1(S) s.c. Tumors (250 mm3) were used. Treatments with PF-06463992 at various doses were applied consecutively for 7 or 9 d. At dosages of 0.2 to 1 mg/kg/d, PF-06463922 significantly inhibited the growth of both established FIGROS1(S) and CD74-ROS1 tumors compared with vehicle control. At 2-6 mg/kg/d, PF-06463922 significantly made tumor volumes regress (58–85%, P < 0.0001). In animals bearing NIH 3T3-CD74-ROS1G2032R tumors, treatment with PF-06463922 at 1.0, 3.0, and 10 mg/kg/d significantly inhibited tumor growth by 28%, 44% and 90%, respectively. At 30 mg/kg/d, PF-06463922 made tumor regress by 12%, compared with vehicle [1].

References:
[1].  Zou HY, Li Q, Engstrom LD, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proceedings of the National Academy of Sciences, 2015, 112(11): 3493-3498.
[2].  Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non–small cell lung cancer. Clinical Cancer Research, 2012, 18(17): 4570-4579.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt406.41
Cas No.1454846-35-5
FormulaC21H19FN6O2
Synonymslorlatinib
Solubility≥20.3mg/mL in DMSO
SDFDownload SDF
Canonical SMILESFC1=CC([C@H](OC2=C(N)N=CC(C3=C(C#N)N(C)N=C3CN4C)=C2)C)=C(C4=O)C=C1
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

携带SLC34A2-ROS1(S/L)蛋白的HCC78细胞和表达CD74-ROS1融合物的BaF3细胞

溶解方法

在DMSO中的溶解度>20.3mg/mL。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

0-10000 nM

应用

在HCC78和BaF3 CD74-ROS1细胞中,PF-06463922有效抑制细胞增殖,IC50值分别为1.3和0.6nM。PF-06463922剂量依赖性地降低HCC78细胞中SLC34A2-ROS1和下游信号分子SHP2,Erk1/2和AKT的磷酸化。

动物实验[1]:

动物模型

携带FIG-ROS1多形性成胶质细胞瘤(GBM)肿瘤的小鼠

剂量

10 mg/kg/d; 皮下渗透泵; 3、7或14天治疗

应用

在携带FIG-ROS1 GBM肿瘤的小鼠中,PF-06463922在7-d和14-d治疗后显著回归GBM LSL-FIG-ROS1;Cdkn2a-/-;LSL-Luc肿瘤。PF-06463922降低整体肿瘤细胞大小和Ki67阳性细胞数。PF-06463922在肿瘤细胞裂解物中减少pFIG-ROS1,pSHP2,pMEK1/2和pERK1/2。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同,这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Zou HY, Li Q, Engstrom LD, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proceedings of the National Academy of Sciences, 2015, 112(11): 3493-3498.

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