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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Mitochondrial RNA polymerase (POLRMT) is upregulated in prostate cancer (PCa), identifying it as a potential therapeutic target.
• Understanding POLRMT's role is crucial for developing novel PCa treatments.

Purpose of the Study:

• To design, optimize, and evaluate novel POLRMT inhibitors for prostate cancer therapy.
• To assess the antiproliferative and therapeutic efficacy of the lead compound YH-0623.

Main Methods:

• Rational design and optimization of POLRMT inhibitors.
• In vitro evaluation of antiproliferative effects on 22Rv1 cells.
• Assessment of mitochondrial gene expression and OXPHOS protein levels.
• Pharmacokinetic profiling and in vivo efficacy studies in a PCa xenograft mouse model.

Main Results:

• The compound YH-0623 exhibited potent antiproliferative activity against 22Rv1 cells.
• YH-0623 significantly reduced mitochondrial gene expression, cell growth, colony formation, and OXPHOS proteins.
• YH-0623 demonstrated excellent oral bioavailability (88.9%) and significant tumor growth inhibition in vivo.
• The compound showed a favorable pharmacokinetic profile and therapeutic efficacy in a PCa xenograft model.

Conclusions:

• Novel POLRMT inhibitors, particularly YH-0623, represent a promising new class of therapeutics for prostate cancer.
• YH-0623's potent activity, favorable pharmacokinetics, and in vivo efficacy support its further development for PCa treatment.