生物活性

Dovitinib (TKI-258, CHIR-258)是一种多靶点的RTK抑制剂，对III型(FLT3/c-Kit)作用最强，IC50为1 nM/2 nM，同时也作用于IV类(FGFR1/3)和V类(VEGFR1-4) RTKs，IC50为8-13 nM，但对InsR， EGFR， c-Met， EphA2， Tie2， IGF-1R和HER2作用较弱。Dovitinib有效抑制FGFR1/3和VEFFR1-2，IC50为8-13 nM。Dovitinib对InsR, EGFR, c-Met, EphrinA2, Tie2, IGFR1,和HER2抑制效果不大。Dovitinib作用于FGF刺激的野生型B9细胞和F384L突变型B9细胞的生长显示出强细胞毒性，IC50为25 nM。

 

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	J807C, Y373C, K650E, G384D, wild type (WT), F384L and B9-MINV cells
方法	Viability assay. Cell viability was assessed by 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) dye absorbance according to the manufacturer's instructions (Boehringer Mannheim, Mannheim, Germany). Cells were seeded in 96-well plates at a density of 5000 (B9 cells) or 20 000 (MM cell lines) cells per well. Cells were incubated with 30 ng/mL aFGF and 100 μg/mL heparin or 1% IL-6 where indicated and increasing concentrations of CHIR-258. For each concentration of CHIR-258, 10-μL aliquots of drug or DMSO diluted in culture medium was added. For drug combination studies, cells were incubated with 0.5 μM dexamethasone, 100 nM CHIR-258, or both simultaneously where indicated. To evaluate the effect of CHIR-258 on growth of MM cells adherent to BMSCs, 10 000 KMS11 cells were cultured on BMSC-coated 96-well plates in the presence or absence of CHIR-258. Plates were incubated for 48 to 96 hours.
浓度	0~400 n M
处理时间	48 h

动物实验
动物模型	KMS11 cells xenograft mouse model
配制	5 mM citrate buffer
剂量	10, 30, or 60 mg/kg daily for 21 days
给药处理	oral gavage

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Km系数（3），再除以大鼠的Km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

分子量	392.43
分子式	C21H21FN6O
CAS号	405169-16-6
纯度	>99%

溶解性（25°C）	DMSO 30 mg/mL
储存和运输条件	固体粉末： -20°C 冷藏长期储存 常温运输及临时存放

 

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	2.5482 mL	12.7411 mL	25.4823 mL
5 mM	0.5096 mL	2.5482 mL	5.0965 mL
10 mM	0.2548 mL	1.2741 mL	2.5482 mL

 

参考文献

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
Sivanand et al. Sci Transl Med. 2012 Jun 6;4(137):137ra75. PMID: 22674553.

Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib.
Wang et al. J Clin Pharmacol. 2012 Jan 27. PMID: 22287694.

Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3.
Chen et al. Biochem Pharmacol. 2012 Mar 15;83(6):769-77. PMID: 22230479.

Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3.
Tai et al. Mol Cancer Ther. 2012 Feb;11(2):452-63. PMID: 22180308.

Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma.
Huynh et al. J Hepatol. 2012 Mar;56(3):595-601. PMID: 22027573.

Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.
Kim et al. Clin Cancer Res. 2011 Dec 1;17(23):7451-61. PMID: 21976540.

CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
Trudel S, et al. Blood. 2005 Apr 1;105(7):2941-8. PMID: 15598814.

Attribute
[Chem Name]	Dovitinib(TKI-258,CHIR-258)
[Synonym]	多韦替尼碱,度维替尼
[CAS No.]	405169-16-6
[Formula]	C21H21FN6O
[Molecular]	392.43
[Storage]	密封保存

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