Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma

• Published in: Drug design, development and therapy development and therapy, 2020-01, Vol.14, p.1779-1798
• Main Authors: Feng, Ying-Qi, Gu, Shuang-Xi, Chen, Yong-Shou, Gao, Xu-Dong, Ren, Yi-Xin, Chen, Jian-Chao, Lu, Yin-Ying, Zhang, Heng, Cao, Shuang
• Format: Article
• Language: English
• Subjects: Analysis; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; hcc; Hepatocellular carcinoma; Humans; Ionizing radiation; kinase inhibitor; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Models, Molecular; Molecular Structure; mtor; Original Research; Pyrimidines; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Radiation-Sensitizing Agents - chemical synthesis; Radiation-Sensitizing Agents - chemistry; Radiation-Sensitizing Agents - pharmacology; radiosensitizer; Radiotherapy; Structure-Activity Relationship; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; virtual docking
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S249156

Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound ( ) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound , with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC =7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.