Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Some tumors rely on high oxidative phosphorylation (OXPHOS) for energy, especially slow-cycling cells.
• Targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression is a potential cancer therapy strategy.

Purpose of the Study:

• To explore and optimize the first-in-class POLRMT inhibitor IMT1B.
• To identify novel compounds with potent antiproliferative effects against cancer cells.

Main Methods:

• Structure-activity relationship (SAR) studies were performed on IMT1B.
• The novel compound D26 was synthesized and tested for antiproliferative activity.
• Mechanism of action studies were conducted in A2780 cells.
• In vivo efficacy and toxicity studies were performed in A2780 xenograft nude mice.

Main Results:

• Compound D26 demonstrated strong antiproliferative effects on various cancer cells.
• D26 inhibited mitochondrial gene expression and arrested cell cycle at the G1 phase.
• D26 showed enhanced anticancer activity compared to IMT1B in vivo with no observable toxic effects.

Conclusions:

• D26 is a potent POLRMT inhibitor with significant anticancer activity.
• D26 represents a promising and safe antitumor candidate for further investigation.