Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers

• 成果类型: Article
• 署名作者: Ruan, Mei-Ling; Ni, Wen-Xiu; Chu, Jacky C. H.; Lam, Tsz-Lung; Law, Kwok-Chung; Zhang, Yiwei; Yang, Guanya; He, Ying; Zhang, Chunlei; Fung, Yi Man Eva; Liu, Tao; Huang, Tao; Lok, Chun-Nam; Chan, Sharon Lai-Fung; Che, Chi-Ming
• 署名单位: University of Hong Kong; University of Hong Kong; Central China Normal University; Shantou University; Chemistry & Chemical Engineering Guangdong Laboratory; Hong Kong Polytechnic University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14181
• DOI: 10.1073/pnas.2316615121
• 发表日期: 2024-06-18
• 关键词: g-alpha-i; giv; activation; expression; identification; receptors; migration; motility; PATHWAY

摘要

Many cancer- driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three- dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium- N- heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient- derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non- small- cell lung cancer and triple- negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody- drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small- molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 mu M and targets the Girdin- linked EGFR/AKT/mTOR/STAT3 cancer- driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin- targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small- molecule inhibitors that can fit into the ligand- binding pockets of key oncoproteins.