中文名称:

4-[6-[4-[(甲氧羰基)氨基]苯基]-4-(4-吗啉基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶羧酸甲酯

中文同义词:

4-[6-[4-[(甲氧羰基)氨基]苯基]-4-(4-吗啉基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶羧酸甲酯;MTOR抑制剂(WYE-354)

英文名称:

WYE-354

英文同义词:

WYE-354;4-[6-[4-[(Methoxycarbonyl)amino]phenyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylic acid methyl ester;methyl 4-[6-[4-(methoxycarbonylamino)phenyl]-4-morpholin-4-ylpyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate;WYE-354 (Degrasyn);WYE-354;WYE 354; WYE354;CS-441;Methyl 4-(6-(4-(methoxycarbonylamino)phenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pip;1-Piperidinecarboxylic acid, 4-[6-[4-[(methoxycarbonyl)amino]phenyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-, methyl ester

CAS号:

1062169-56-5

分子式:

C24H29N7O5

分子量:

495.53

EINECS号:

相关类别:

小分子抑制剂，天然产物;细胞生物学试剂;Amines;Aromatics;Heterocycles;Intermediates Fine Chemicals;Pharmaceuticals;Protein Kinase Inhibitors and Activators;PI3K/Akt/mTOR;Inhibitors;Akt;mTOR;PI3K

Mol文件:

1062169-56-5.mol

密度 

1.46

储存条件 

Sealed in dry,Store in freezer, under -20°C

酸度系数(pKa)

13.42±0.70(Predicted)

生物活性

WYE-354 是一种 ATP 竞争性的 mTOR 抑制剂，IC50 为 5 nM。WYE-354 也抑制 PI3Kα 和 PI3Kγ，IC50 分别为 1.89 μM 和 7.37 μM。WYE-354 抑制 mTORC1 和 mTORC2。WYE-354 在体外能诱导自噬 (autophagy) 激活.

靶点

mTOR 5 nM (IC 50 ) mTORC1 mTORC2 PI3K alpha 1.89 μM (IC 50 ) PI3K gamma 7.37 μM (IC 50 ) Autophagy

mTOR 5 nM (IC 50 )

mTORC1

体外研究

In the DELFIA measuring His6-S6K1 T389 phosphorylation, WYE-354 inhibits recombinant mTOR enzyme with an IC 50 of 5 nM. Cell viability is analyzed by MTS assay. G-415 and TGBC-2TKB cell lines are treated with increasing concentrations of WYE-354 (0.1, 1, 5 and 10 μM) for 24, 48, and 72 hours. WYE-354 significantly reduces cell viability starting at a 1 μM concentration after a 24 hours exposure, in both studied cell lines (P<0.001). A decrease in cell viability is not observed at a dose of 100 nM, except for the TGBC-2TKB cell line after 72 hours of treatment.

体内研究

The effect of Rapamycin and WYE-354 on tumor growth is evaluated in xenograft GBC tumor models. 2×10 6 or 5×10 6 cells of G-415 or TGBC2TKB, respectively, are xenotransplanted into NOD-SCID mice subcutaneously. When tumors reach an average volume of 100 mm 3 , the mice are treated either with Rapamycin or WYE354. Rapamycin is administered i.p. at a concentration of 10 mg/kg, daily for 5 days per week for 3 weeks, while WYE-354 is administrated at a daily i.p. dose of 50 mg/kg for 5 days. Mice are sacrificed 30 days after the initiation of the treatments and an autopsy is performed that include removal of the entire tumor area. Mice treated with WYE-354 exhibit 68.6% and 52.4% reduction in average tumor size (P<0.01; P<0.01), as well as 82.9% and 45.5% (P<0.01; ns) reduction in tumor weight, respectively.

用途 

A pyrazolopyrimidines derivative that is a potent and ATP-competitive mTOR inhibitor with much reduced activity against PI 3-Kα or PI 3-Kγ. WYE-354 is equally potent against mTORC1 and mTORC2 activiti es in HEK293 immune complex kinase assays using S6K and Akt as the respective substrate (IC50 <200 nM; [ATP] = 100 碌M) and effectively blocks cellular phosphorylation of S6K on T389 and Akt on S473 bo th in cultures and in a murine xenograft model, resulting in a significant suppression of PC3MM2-derived tumor growth (by 86% on day 7; 50 mg/kg, i.p twice per day) in vivo.