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

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.