1. Identification of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer.
- Author
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Zhou S, Ze X, Feng D, Liu L, Shi Y, Yu M, Huang L, Wang Y, Men H, Wu J, Yuan Z, Zhou M, Xu J, Li X, and Yao H
- Subjects
- Humans, Animals, Structure-Activity Relationship, Cell Line, Tumor, Mice, Mice, Nude, Fluorine chemistry, Apoptosis drug effects, Reactive Oxygen Species metabolism, Xenograft Model Antitumor Assays, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors therapeutic use, Membrane Potential, Mitochondrial drug effects, Mice, Inbred BALB C, Drug Screening Assays, Antitumor, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use, Coumarins pharmacology, Coumarins chemistry, Coumarins chemical synthesis, Coumarins therapeutic use, Cell Proliferation drug effects, DNA-Directed RNA Polymerases antagonists & inhibitors, DNA-Directed RNA Polymerases metabolism
- Abstract
Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7 , which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.
- Published
- 2024
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