Yang Xiyue, Wang Linghui, Lin Peiyu, Ning Yueni, Lin Yusi, Xie Yingying, Zhao Congke, Mu Lingli, Xu Cangcang
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Pharmaceutical Sciences, Health Science Center, Hunan Normal University, Changsha, 410013, Hunan, China.
Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
Eur J Med Chem. 2025 Sep 5;293:117710. doi: 10.1016/j.ejmech.2025.117710. Epub 2025 May 3.
Bladder cancer is the second most prevalent malignancy of the urinary system worldwide, with high incidence and mortality rates. However, existing drugs for bladder cancer treatment often cause numerous adverse reactions. Although artesunate (ARS) exhibits anti-bladder cancer activity, its scope is rather limited and the specific targets remain unclear. Therefore, in this study, the Proteolysis-Targeting Chimera (PROTAC) technology was used to design and synthesize novel ARS derivatives. The antitumor activities of these compounds were evaluated against three human bladder cancer cell lines (T24, RT4, and J82). Of these compounds, A7 exhibited 12-fold stronger antiproliferative activity against bladder cancer cells than ARS. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA) and western blotting studies demonstrated that A7 directly targeted and degraded glutathione peroxidase 4 (GPX4) protein through the ubiquitin-proteasome system. A7 further induced bladder cancer cell ferroptosis. Furthermore, A7 showed potent tumor suppressive activity in a xenograft T24 nude mouse model. In conclusion, our findings indicate that A7 exerts notable antitumor effects against bladder cancer in vitro and in vivo. This study highlights the tremendous potential of the PROTAC technology in enhancing the efficacy of natural products and identifying therapeutic targets, demonstrating its broad application prospects in the development of natural products-based drugs.
膀胱癌是全球泌尿系统中第二常见的恶性肿瘤，发病率和死亡率都很高。然而，现有的膀胱癌治疗药物常常会引发众多不良反应。尽管青蒿琥酯（ARS）具有抗膀胱癌活性，但其作用范围相当有限，具体靶点仍不清楚。因此，在本研究中，利用蛋白酶靶向嵌合体（PROTAC）技术设计并合成了新型ARS衍生物。针对三种人膀胱癌细胞系（T24、RT4和J82）评估了这些化合物的抗肿瘤活性。在这些化合物中，A7对膀胱癌细胞的抗增殖活性比ARS强12倍。分子对接、表面等离子体共振（SPR）、细胞热位移分析（CETSA）和蛋白质印迹研究表明，A7通过泛素-蛋白酶体系统直接靶向并降解谷胱甘肽过氧化物酶4（GPX4）蛋白。A7进一步诱导膀胱癌细胞发生铁死亡。此外，A7在异种移植T24裸鼠模型中显示出强大的肿瘤抑制活性。总之，我们的研究结果表明，A7在体外和体内对膀胱癌均具有显著的抗肿瘤作用。本研究突出了PROTAC技术在提高天然产物疗效和确定治疗靶点方面的巨大潜力，展示了其在基于天然产物的药物开发中的广阔应用前景。
