PF-04217903

生物活性

PF-04217903是一种选择性的，ATP竞争性c-Met抑制剂，IC50为4.8 nM，对致癌基因突变型敏感(对Y1230C突变型没有活性)。PF-04217903选择性比Staurosporine或PF-02341066高, PF-04217903作用于c-Met选择性比作用于其他一组208种激酶选择性高1000多倍，对c-Met致癌突变更敏感 。除了作用于WT c-Met,PF-04217903也有效抑制 c-Met-H1094R, c-Met-R988C, 和c-Met-T1010I 活性，IC50分别为3.1 nM, 6.4 nM, 和 6.7 nM,但是对c-Met-Y1230C几乎没有抑制效果，IC50 >10 μM。 PF-04217903 和Sunitinib联用显著抑制内皮细胞增殖, 但是不抑制肿瘤细胞B16F1, Tib6, EL4, 和 LLC。

实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）

细胞实验
细胞系	B16F1, Tib6, EL4, and LLC, and endothelial cells, HUVECs and C166
方法	Cell lines, including B16F1, Tib6, EL4, and LLC, and endothelial cells, HUVECs and C166, were seeded at 104 cells in each well of 24-well tissue culture–treated plates. Cells were grown in the standard media as described earlier. Cells were treated with different concentrations (2, 0.2, and 0.02 μmol/L) of sunitinib, PF-04217903, and combination of both compounds for 4 days. Efficacy of the compounds was measured by counting cells in a Coulter counter machine (BD Biosciences). Similar approach was applied to evaluate the role of HGF or VEGF on cell proliferation, using 3 different concentrations (10, 100, and 200 ng/mL) of each ligand.
浓度	2, 0.2, and 0.02 μmol/L
处理时间	4 days

动物实验
动物模型	B16F10 tumour-bearing mice
配制	0.5% methylcellulose in saline
剂量	40mg/kg PF-04217903
给药处理	oral

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

	小鼠	大鼠	兔	豚鼠	仓鼠	狗
重量 (kg)	0.02	0.15	1.8	0.4	0.08	10
体表面积 (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km 系数	3	6	12	8	5	20

动物 A (mg/kg) = 动物 B (mg/kg) ×	动物 B的Km系数
	动物 A的Km系数

例如，依据体表面积折算法，将白藜芦醇用于小鼠的剂量22.4 mg/kg 换算成大鼠的剂量，需要将22.4 mg/kg 乘以小鼠的K_m系数（3），再除以大鼠的K_m系数（6），得到白藜芦醇用于大鼠的等效剂量为11.2 mg/kg。

化学数据

储备液配制

以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	2.6854 mL	13.4271 mL	26.8543 mL
5 mM	0.5371 mL	2.6854 mL	5.3709 mL
10 mM	0.2685 mL	1.3427 mL	2.6854 mL

使用AbMole产品发表的文献

• 

  Elife. 2019 Sep 19;8. pii: e47460.

  A distinct cardiopharyngeal mesoderm genetic hierarchy establishes antero-posterior patterning of esophagus striated muscle.
  PF-04217903购买自AbMole

• 

  Nature. 2015 Jun 18;522(7556):349-53.

  MET is required for the recruitment of anti-tumoural neutrophils.
  PF-04217903购买自AbMole

客户产品验证及相关生物数据

	数据来源	Nature (2015). Figure 3. PF-04217903 and INCB28060 (AbMole Bioscience)
	方法	mice treatment in vivo and histological evaluation
	细胞系	B16F10 cells
	浓度	40mg/kg PF-04217903 and 50mg/kg INCB28060
	处理时间	2 weeks
	实验结果	Systemic treatment of WT mice carrying B16F10 melanomas (which are dependent on MET14) with three different MET tyrosine-kinase inhibitors (PF-04217903, INCB28060 and JNJ-38877605), strongly reduced TAN recruitment .

	数据来源	Nature (2015). Figure 2. PF-04217903 and INCB28060 (AbMole Bioscience)
	方法	mice treatment in vivo and histological evaluation
	细胞系	B16F10 cells
	浓度	40mg/kg PF-04217903
	处理时间	2 weeks
	实验结果	"Systemic administration of PF-04217903 decreased the weight and volume of B16F10 melanomas by 36% and 54%, respectively. Instead, MET knockdown in cancer cells only, led to 58% and 75% inhibition of tumour growth and volume.TAN inhibition by PF-04217903 was comparable in both Met-silenced and scrambled B16F10 melanomas."

参考文献

Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer.
Cui JJ, et al. J Med Chem. 2012 Sep 27;55(18):8091-109. PMID: 22924734.

A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells though MAPK activation.
Lee NV, et al. PLoS One. 2012;7(6):e39653. PMID: 22745804.