N-[4-[1-(1,4-二氧杂螺[4.5]癸烷-8-基)-4-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-1H-吡唑并[3,4-D]嘧啶-6-基]苯基]-N'-甲基脲性质、用途与生产工艺
WYE-125132 (WYE-132)是一种高度有效的,ATP竞争性的mTOR抑制剂,IC50为0.19 nM;作用于mTOR比作用于PI3Ks或PI3K相关激酶hSMG1和ATR选择性高。
WYE-125132 potently and ATP-competitively inhibits recombinant mTOR kinase with IC50 of 0.19 nM and also shows the high selectivity over various PI3Ks and a panel of 230 protein kinases. In vitro, WYE-125132 exhibits a significant anti-proliferative activity against a panel of tumor cell lines with IC50 ranging from 2 nM (LNCap) to 380 nM (HTC116). Besides, WYE-125132 also causes cell cycle progression, induction of apoptosis, and inhibition of protein synthesis and cell size. WYE-125132 results in a significant reduction in the synthesis of pre-tRNA
Leu by 72%, 80%, and 53% in actively proliferating cells of MG63, MDA361, and HEK293, respectively by inhibiting mTORC1. Moreover, WYE-125132 is also found to induce the dephosphorylation of Maf1 (negative regulator of Pol III transcription) and its accumulation in the nucleus.
WYE-125132 (5 mg/kg p.o.) produces significant antitumor activity and causes dose-dependent tumor growth delay in the PI3K/mTOR- and HER2-hyperactive MDA361 tumor model. In addition, WYE-125132 also shows potent antitumor efficacy in the PTEN-null glioma U87MG, non-small cell lung cancer H1975 and A549 models.
WYE-125132 is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor.
WYE-125132 (WYE-132)是一种高度有效的,ATP竞争性的mTOR抑制剂,IC50为0.19 nM;作用于mTOR比作用于PI3Ks或PI3K相关激酶hSMG1和ATR选择性高。
Target | Value |
mTOR
(Cell-free assay)
|
0.19 nM
|
WYE-125132强效且ATP竞争性抑制重组mTOR激酶,IC50 为0.19 nM,选择性比作用于各种PI3Ks和230个蛋白激酶组高。在体外,WYE-125132对一组肿瘤细胞系表现出显著的抗增殖活性,IC50 范围为2 nM (LNCap) 到380 nM (HTC116)。此外,WYE-125132也会引起细胞周期进程,细胞凋亡诱导,以及蛋白合成和细胞大小的抑制。 WYE-125132通过抑制mTORC1引起pre-tRNA
在PI3K/mTOR- 和HER2-极度活跃的MDA361肿瘤模型中,WYE-125132(5 mg/kg p.o.)产生显著的抗肿瘤活性,并引起肿瘤生长剂量依赖性延缓。此外,WYE-125132在PTEN缺失的胶质瘤U87MG,非小细胞肺癌H1975 和A549模型中表现出有效的抗肿瘤活性。
N-[4-[1-(1,4-二氧杂螺[4.5]癸烷-8-基)-4-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-1H-吡唑并[3,4-D]嘧啶-6-基]苯基]-N'-甲基脲
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