Ni Sha, Qu Hui, Liu Da, Yuan Lin, Li Mengqi, Zhao Wancheng
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, China.
Eur J Med Chem. 2025 Nov 15;298:118046. doi: 10.1016/j.ejmech.2025.118046. Epub 2025 Aug 6.
The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, serves as a central regulator of cellular growth, proliferation, metabolism, and survival through its two distinct multiprotein complexes, mTORC1 and mTORC2. Aberrant activation of the mTOR signaling pathway is frequently implicated in a wide range of human cancers and is closely associated with tumor progression, therapeutic resistance, and poor clinical outcomes. Accordingly, pharmacological inhibition of mTOR has emerged as a compelling strategy in the development of anticancer therapeutics. To date, several mTOR inhibitors have received regulatory approval or are currently undergoing clinical evaluation. This review provides an up-to-date development of small-molecule mTOR inhibitors from 2019 to the present. Emphasis is placed on their structural classification, mechanisms of action, and medicinal chemistry optimization strategies. We believe that this review, together with previous summaries from other research groups, will offer valuable insights to support the rational design and development of next-generation mTOR inhibitors with improved pharmacokinetic properties and enhanced target selectivity.
雷帕霉素的作用靶点（mTOR）是一种丝氨酸/苏氨酸激酶，通过其两种不同的多蛋白复合物mTORC1和mTORC2，作为细胞生长、增殖、代谢和存活的核心调节因子。mTOR信号通路的异常激活常常与多种人类癌症相关，并且与肿瘤进展、治疗耐药性及不良临床预后密切相关。因此，mTOR的药理学抑制已成为抗癌治疗药物开发中一种引人注目的策略。迄今为止，几种mTOR抑制剂已获得监管批准或正在进行临床评估。本综述提供了2019年至今小分子mTOR抑制剂的最新进展。重点介绍了它们的结构分类、作用机制和药物化学优化策略。我们相信，本综述与其他研究小组之前的总结一起，将提供有价值的见解，以支持具有改善药代动力学性质和增强靶点选择性的下一代mTOR抑制剂的合理设计与开发。
