Abnormal activation of the mechanistic target of rapamycin (mTOR) signaling is commonly observed in many cancers and attracts extensive attention as an oncology drug discovery target, which is encouraged by the success of rapamycin and its analogs (rapalogs) in treatment of mTORC1-hyperactive cancers in both pre-clinic models and clinical trials. However, rapamycin and existing rapalogs have typically short-lasting partial responses due to drug resistance, thereby triggering our interest to investigate a potential mTORC1 inhibitor that is mechanistically different from rapamycin. Here, we report that hayatine, a derivative from Cissampelos, can serve as a potential mTORC1 inhibitor selected from a natural compound library. The unique properties owned by hayatine such as downregulation of mTORC1 activities, induction of mTORC1's translocation to lysosomes followed by autophagy, and suppression on cancer cell growth, strongly emphasize its role as a potential mTORC1 inhibitor. Mechanistically, we found that hayatine disrupts the interaction between mTORC1 complex and its lysosomal adaptor RagA/C by binding to the hydrophobic loop of RagC, leading to mTORC1 inhibition that holds great promise to overcome rapamycin resistance. Taken together, our data shed light on an innovative strategy using structural interruption-based mTORC1 inhibitors for cancer treatment.

雷帕霉素机制靶点 (mTOR) 信号传导的异常激活在许多癌症中很常见，并且作为肿瘤药物发现靶点而受到广泛关注，这得益于雷帕霉素及其类似物（rapalogs）在治疗 mTORC1 过度活跃癌症中的成功在临床前模型和临床试验中。然而，由于耐药性，雷帕霉素和现有的雷帕霉素类似物通常具有短暂的部分反应，从而引发了我们研究一种在机制上与雷帕霉素不同的潜在 mTORC1 抑制剂的兴趣。在这里，我们报道了来自Cissampelos的衍生物 hayatin，可以作为从天然化合物库中选择的潜在 mTORC1 抑制剂。 hayatine 拥有的独特特性，例如下调 mTORC1 活性、诱导 mTORC1 易位至溶酶体并随后自噬以及抑制癌细胞生长，强烈强调了其作为潜在 mTORC1 抑制剂的作用。从机制上讲，我们发现，hayatine 通过与 RagC 的疏水环结合，破坏 mTORC1 复合物与其溶酶体接头 RagA/C 之间的相互作用，从而抑制 mTORC1，从而有望克服雷帕霉素耐药性。总而言之，我们的数据揭示了使用基于结构中断的 mTORC1 抑制剂进行癌症治疗的创新策略。