AST 487

中文名称:

AST 487

中文同义词:

RET激酶抑制剂(AST 487);N-[4-[(4-ETHYL-1-PIPERAZINYL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL]-N-[4-[[6-(METHYLAMINO)-4-PYRIMIDINYL]OXY]PHENYL]UREA;化合物AST 487

英文名称:

AST 487

英文同义词:

AST 487;NVP-AST 487;1-{4-[(4-Ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl}-3-(4-{[6-(methylamino)-4-pyrimidinyl]oxy}phenyl)urea;1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)urea;3-{4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}-1-(4-{[6-(METHYLAMINO)PYRIMIDIN-4-YL]OXY}PHENYL)UREA;CS-562;Urea,N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-;N-[4-[(4-Ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea

CAS号:

630124-46-8

分子式:

C26H30F3N7O2

分子量:

529.56

EINECS号:

205-525-8

相关类别:

细胞生物学试剂

Mol文件:

630124-46-8.mol

沸点 

563.1±50.0 °C(Predicted)

密度 

1.341±0.06 g/cm3(Predicted)

储存条件 

Inert atmosphere,2-8°C

酸度系数(pKa)

13.33±0.70(Predicted)

生物活性

AST-487 (NVP-AST487)，一种N,N-二苯基脲，是Flt3的竞争性抑制剂，ki值为0.12 μM。除FLT3以外，AST487还抑制RET,KDR,c-KIT 和 c-ABL 激酶，IC50值低于1 μM。

靶点

Target Value RET () KDR () c-Kit () c-Abl () FLT3 (Cell-free assay) 0.12 μM(Ki)

Target

Value

RET ()

KDR ()

c-Kit ()

c-Abl ()

FLT3 (Cell-free assay)

0.12 μM(Ki)

体外研究

A number of other kinases are also similarly inhibited by AST 487 (NVP-AST487) in the in vitro kinase assays, including KDR (IC 50 =170 nM), Flt-4 (IC 50 =790 nM), Flt-3 (IC 50 =520 nM), c-Kit (IC 50 =500 nM), and c-Abl (IC 50 =20 nM). AST 487 potently inhibits the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. Both GDNF/GFRα1 and persephin-induced calcitonin mRNA are markedly inhibited by coincubation with 100 nM of AST 487 in MTC-M cells. AST 487 is a novel, mutant FLT3 inhibitor. AST 487 is tested in biochemical assays for inhibition of Flt-3 kinase activity. The K i is determined to be 0.12 μM. Besides Flt-3, NVP-AST487 inhibits RET, KDR, c-Kit, and c-Abl kinase with IC 50 values below 1 μM. Treatment of FLT3-ITD-Ba/F3 cells and D835Y-Ba/F3 cells with AST 487 potently inhibits cellular proliferation (IC 50 <5 nM). AST 487 treatment of FLT3-ITD-Ba/F3 cells with 0.01 μM AST 487 results in complete cell killing compare with approximately 50% killing of AML patient samples at the same concentration.

体内研究

After a single oral administration of 15 mg/kg of AST 487 to OF1 mice, a mean peak plasma level (C max ) of 0.505±0.078 μM SE is achieved after 0.5 h. Similar levels of AST 487 are found in the plasma of mice up to 6 h after oral administration, with a C last of 21±4 nM at 24 h. The oral bioavailability is calculated to be 9.7% with a t 1/2 terminal elimination of 1.5 h.