2. Academic Validation
  3. Design, Optimization, and Biological Evaluation of a Novel Quinoline-Based POLRMT Inhibitor for Prostate Cancer Therapy

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

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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