Fold-Stabilized Zn(II) Metallohelices Inhibit mTOR Signaling and Modulate the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma
Xue Zhao, Zixuan Wang, Mi Li, Jingwen Wang, Zijing Xu, Yifan Song, Changhao Liu, Xuebin Wang, Chenxu Niu, Louchenghan Hu, Yukun Deng, Jingxuan Qi, Zifan Feng, Miles L. Postings, Nicola J. Rogers, Peter Scott, Xinhua Song, Rubing Wang, Hualong SongAbstract
Water-stabilized metallohelices based on labile metal ions remain rare because of hydrolytic instability. Here, we report the design and synthesis of a unique class of optically pure, water-soluble, glycosylated Zn(II) metallohelix diastereomers that exhibit exceptional hydrolytic stability and potent, stereochemistry-dependent antiproliferative activity against intrahepatic cholangiocarcinoma (ICC). In an orthotopic, AKT/YAP-driven ICC mouse model, treatment with the lead compound Λ-7a produced significant tumor growth inhibition. Mechanistic studies revealed that treatment with Λ-7a induced cell cycle arrest and apoptosis, accompanied by suppression of PI3K-AKT-mTOR pathway signaling and reduced phosphorylation of downstream effectors. In addition, Λ-7a treatment was associated with reduced vascular and stromal marker staining and increased CD8+ T-cell and macrophage markers within the tumor microenvironment. Together, these results establish fold-stabilized Zn(II) metallohelices as a new class of metallodrugs exhibiting potent anti-ICC activity, suppression of AKT/mTOR pathway signaling, and treatment-associated changes in vascular, stromal, and immune-cell markers within the tumor microenvironment.