1-[4-[4-(1-氧代丙基)-1-哌嗪基]-3-(三氟甲基)苯基]-9-(3-喹啉基)苯并[H]-1,6-萘啶-2(1H)-酮

Torin 1是一种有效的mTORC1/2抑制剂，IC50为2 nM/10 nM；作用于mTOR比作用于PI3K选择性高1000倍。 Torin1 inhibits phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin1 causes cell cycle arrest through a rapamycin-resistant mechanism that is also independent of mTORC2. Torin1 disrupts mTORC1-dependent phenotypes more completely than rapamycin. Rapamycin-resistant functions of mTORC1 are required for cap-dependent translation. In a recent study, it is reported Torin1 increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON. Torin1 is efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrates good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. Torin 1是一种有效的mTORC1/2抑制剂，在无细胞试验中IC50为2 nM/10 nM；作用于mTOR比作用于PI3K选择性高1000倍。

Target	Value
mTORC1 (Cell-free assay)	2 nM
mTOR (Cell-free assay)	4.32 nM
DNA-PK (Cell-free assay)	6.34 nM
mTORC2 (Cell-free assay)	10 nM
p110γ (Cell-free assay)	171 nM

Torin1在2和10 nM浓度下分别抑制mTORC1 和mTORC2底物的磷酸化。此外，Torin1对mTOR比对PI3K (EC50 = 1800 nM)的选择性高1000倍，比对450种其它蛋白激酶的结合选择性高100倍。 Torin1通过耐rapamycin机制引起细胞周期阻滞，并且其不依赖于mTORC2。Torin1比rapamycin更完全地干扰mTORC1依赖表现型。Cap依赖性翻译需要mTORC1耐Rapamycin的功能。在近期的一项研究中，据报道Torin1通过活化人内分泌细胞系BON 中MEK/ERK/c-Jun通路，能够增加神经降压素分泌和基因表达。

Torin1在20 mg/kg剂量下，在U87MG异种移植模型中是有效的，并且在肿瘤和外周组织中对mTOR下游效应蛋白表现出良好的药效学抑制作用。