Feng Ying-Qi, Li Bo-An, Feng Fan, Chen Yong-Shou, Ren Yi-Xin, Zhang Heng, Cao Shuang
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430072, People's Republic of China.
Center for Clinical Laboratory, The Fifth Medical Center, General Hospital of Chinese PLA, Beijing 100039, People's Republic of China.
Onco Targets Ther. 2020 Jul 27;13:7165-7176. doi: 10.2147/OTT.S244474. eCollection 2020.
Although molecular-targeted agents are still the first choice for advanced hepatocellular carcinoma (HCC) treatment, the therapeutic efficacy of these agents is not satisfactory. Recently, the mammalian target of rapamycin (mTOR) is considered to be a promising molecular target that can enhance the sensitivity of HCC cells to antitumor therapy. However, the reported mTOR inhibitors have some shortcomings, and novel mTOR inhibitors need to be developed to enhance the antitumor effect of molecularly targeted agents on advanced HCC.
In this study, five small-molecular compounds that could serve as potential mTOR-specific inhibitors were identified by virtual screening. The activity of tert-butyl (4-(9-(2-(1,3-dioxolan-2-yl)ethyl)-6-morpholino-9H-purin-2-yl)phenyl)carbamate (compound ) was measured by enzyme test and Western blot, and its antitumor effect on HCC was examined in nude mice subcutaneous tumor model.
The results showed that is the most effective one in inhibiting the activation of mTOR kinase (mTOR IC = 17.52±3.67 nmol/L) among the five lead compounds. Further research in this study indicated that treatment with enhanced the sensitivity of HCC cells to the molecular-targeted agents, such as sorafenib, regorafenib, lenvatinib, anlotinib, and apatinib. In addition, this research indicated that mTOR was correlated with the poor prognosis in patients with advanced HCC who received sorafenib.
Our study identified a new type of small-molecular inhibitors of mTOR and confirmed their ability to enhance the antitumor effect of molecular-targeted agents on advanced HCC.
尽管分子靶向药物仍是晚期肝细胞癌（HCC）治疗的首选，但这些药物的治疗效果并不理想。最近，雷帕霉素哺乳动物靶点（mTOR）被认为是一个有前景的分子靶点，可增强HCC细胞对抗肿瘤治疗的敏感性。然而，已报道的mTOR抑制剂存在一些缺点，需要开发新型mTOR抑制剂以增强分子靶向药物对晚期HCC的抗肿瘤作用。
在本研究中，通过虚拟筛选鉴定出五种可作为潜在mTOR特异性抑制剂的小分子化合物。采用酶试验和蛋白质免疫印迹法检测叔丁基（4-(9-(2-(1,3-二氧戊环-2-基)乙基)-6-吗啉代-9H-嘌呤-2-基)苯基）氨基甲酸酯（化合物 ）的活性，并在裸鼠皮下肿瘤模型中检测其对HCC的抗肿瘤作用。
结果显示，在这五种先导化合物中， 是抑制mTOR激酶激活最有效的一种（mTOR IC = 17.52±3.67 nmol/L）。本研究的进一步研究表明，用 处理可增强HCC细胞对索拉非尼、瑞戈非尼、仑伐替尼、安罗替尼和阿帕替尼等分子靶向药物的敏感性。此外，本研究表明mTOR与接受索拉非尼治疗的晚期HCC患者的不良预后相关。
我们的研究鉴定出一种新型的mTOR小分子抑制剂，并证实了它们增强分子靶向药物对晚期HCC抗肿瘤作用的能力。
