OncoTargets and Therapy (Jul 2020)

Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents

  • Feng YQ,
  • Li BA,
  • Feng F,
  • Chen YS,
  • Ren YX,
  • Zhang H,
  • Cao S

Journal volume & issue
Vol. Volume 13
pp. 7165 – 7176

Abstract

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Ying-Qi Feng,1,* Bo-An Li,2,* Fan Feng,2,* Yong-Shou Chen,1 Yi-Xin Ren,1 Heng Zhang,1 Shuang Cao1 1Key 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; 2Center for Clinical Laboratory, The Fifth Medical Center, General Hospital of Chinese PLA, Beijing 100039, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Cao; Heng ZhangKey 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 ChinaTel/ Fax +86-18701418117; +86-15994288097Email [email protected]; [email protected]: 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.Methods: 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 4) was measured by enzyme test and Western blot, and its antitumor effect on HCC was examined in nude mice subcutaneous tumor model.Results: The results showed that 4 is the most effective one in inhibiting the activation of mTOR kinase (mTOR IC50 = 17.52± 3.67 nmol/L) among the five lead compounds. Further research in this study indicated that treatment with 4 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.Conclusion: 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.Keywords: hepatocellular carcinoma, mTOR, molecular-targeted agents, virtual screening

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