Identification of mitochondrial ATP synthase as the cellular target of Ru-polypyridyl-β-carboline complexes by affinity-based protein profiling  

作　　者：Wen-Jin Wang Yu-Yi Ling Yin Shi Xiao-Wen Wu Xuxian Su Zheng-Qiu Li Zong-Wan Mao Cai-Ping Tan 

机构地区：[1]MOE Key Laboratory of Bioinorganic and Synthetic Chemistry,School of Chemistry,Sun Yat-Sen University,Guangzhou 510006,China [2]Guangdong Basic Research Center of Excellence for Functional Molecular Engineering,Sun Yat-Sen University,Guangzhou 510006,China [3]School of Pharmacy,MOE Key Laboratory of Tumor Molecular Biology,Jinan University,Guangzhou 510632,China

出　　处：《National Science Review》2024年第8期286-297,共12页国家科学评论（英文版）

基　　金：supported by the National Natural Science Foundation of China (22022707,22177142 and 22307108);Guangdong Basic and Applied Basic Research Foundation (2024B1515040028);the Fundamental Research Funds for the Central Universities.

摘　　要：Ruthenium polypyridyl complexes are promising anticancer candidates,while their cellular targets have rarely been identifed,which limits their clinical application.Herein,we design a series of Ru(II)polypyridyl complexes containing bioactiveβ-carboline derivatives as ligands for anticancer evaluation,among which Rus shows suitable lipophilicity,high aqueous solubility,relatively high anticancer activity and cancer cell selectivity.The subsequent utilization of a photo-clickable probe,RuSa,serves to validate the significance of ATP synthase as a crucial target for RuS through photoaffinity-based protein profling.RuS accumulates in mitochondria,impairs mitochondrial functions and induces mitophagy and ferroptosis.Combined analysis of mitochondrial proteomics and RNA-sequencing shows that RuS significantly downregulates the expression of the chloride channel protein,and influences genes related to ferroptosis and epithelial-to-mesenchymal transition.Finally,we prove that RuS exhibits higher anticancer efficacy than cisplatin in vivo.We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach,which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates.

关 键 词：anticancer agents bimolecular targets chemical proteomics ATPase inhibitor ferroptosis 

分 类 号：R730.5[医药卫生—肿瘤]