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

  • J Med Chem. 2025 Aug 14;68(15):15495-15519. doi: 10.1021/acs.jmedchem.5c00130.
Xinnan Li  1 ,  Lihua Liu  1 ,  Dazhi Feng  1 ,  Yuning Shi  1 ,  Lijuan Huang  1 ,  Minghui Yu  1 ,  Xiawei Fu  2  3 ,  Li Deng  4 ,  Xinyang Nie  1 ,  Cong Chen  1 ,  Yifan Yuan  1 ,  Moyang Guo  1 ,  Chen Chen  1 ,  Yongjie Zhang  4 ,  Fangrong Zhang  2  3 ,  Hong Yao  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
  • 2. Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China.
  • 3. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China.
  • 4. Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
PMID: 40728385 DOI: 10.1021/acs.jmedchem.5c00130
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.

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