Design, Optimization,and Biological Evaluation ofa Novel Quinoline-Based POLRMT Inhibitor for Prostate Cancer Therapy

作者：Xinnan Li, Lihua Liu, Dazhi Feng, Yuning Shi, Lijuan Huang, Minghui Yu, Xudong Fu, Li Deng, Xinyang Nie, Cong Chen, Yifan Yuan, Moyang Guo, Chen Chen, Yongjie Zhang, Fangrong Zhang, Hong Yao · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00130 · 被引用次数：5 · 研究领域：Cancer, Lipids, and Metabolism、Prostate Cancer Treatment and Research、RNA Research and Splicing

Abstract Mitochondrial RNA polymerase (POLRMT) plays a pivotal role in various mitochondrial functions. The upregulation of POLRMT in prostate cancer (PCa) has been well-documented, underscoring its potential as a therapeutic target. In this study, we described the rational design, optimization, and comprehensive biological evaluation of a novel series of POLRMT inhibitors. The most potent compound YH-0623 demonstrated a robust antiproliferative effect on 22Rv1 cell line, correlating with a remarkable reduction in the expression of mitochondrial-related genes. Particularly, YH-0623 significantly inhibited cell growth, colony formation, and the expression of proteins associated with OXPHOS. Furthermore, YH-0623 exhibited a superior pharmacokinetic profile, with an oral bioavailability of 88.9%, indicating favorable absorption upon oral administration. Notably, YH-0623 demonstrated promising therapeutic efficacy, with substantial tumor growth inhibition observed in a PCa xenograft mice model. The potent, selective, and orally available POLRMT inhibitors represent a new class of compounds as potential therapeutics against PCa.