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.
Comprehensive Liver Cancer Department, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, People's Republic of China.
Drug Des Devel Ther. 2020 May 8;14:1779-1798. doi: 10.2147/DDDT.S249156. eCollection 2020.
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.
放射疗法对多种肿瘤具有改善作用，但肝癌（HCC）对此治疗不敏感。过度激活的哺乳动物雷帕霉素靶蛋白（mTOR）在 HCC 对放射疗法的抵抗中起着重要作用；因此，mTOR 抑制剂作为新型放射增敏剂具有增强 HCC 放射治疗效果的潜力。
基于药效基团模型和分子对接发现了一种先导化合物，并根据 mTOR 和 PI3K 的 ATP 结合口袋之间的差异进行优化。通过体外集落形成实验和 DNA 双链断裂实验证实了优化化合物（）的放射增敏作用。描述了该化合物的发现和临床前特征。
确定了 mTOR 中的关键氨基酸残基，并构建了精确的虚拟筛选模型。具有 4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶骨架的化合物 对 mTOR 表现出有前景的效力（mTOR IC=7.1 纳摩尔/升（nM）），对 PI3Kα 的选择性为 126 倍。此外，化合物 在体外以剂量依赖性方式显著增强了 HCC 对放射治疗的敏感性。
开发了一类新型选择性 mTOR 抑制剂，并证实了它们的放射增敏作用。本研究还为开发用于 HCC 放射治疗的 mTOR 特异性抑制剂作为放射增敏剂提供了依据。
