POLRMT inhibitors(China Pharmaceutical University)

The metabolic dependence of acute myeloid leukemia (AML) cells on mitochondrial oxidative phosphorylation (OXPHOS) has become a cutting‐edge area in cancer energy metabolism research, playing a pivotal role in cell survival and drug resistance. Consequently, targeted inhibition of human mitochondrial RNA polymerase (POLRMT) to block mitochondrial gene expression emerges as a novel potential strategy for treating AML through OXPHOS modulation. In this study, based on the previously reported crystal structure of the POLRMT inhibitor IMT1B, we employed a scaffold hopping strategy to design and synthesize a series of derivatives featuring additional hydrophobic occupying groups. A new potent POLRMT inhibitor (10a) was discovered, which displayed potent antiproliferative activity and could disrupt mitochondrial function and induce apoptosis in MOLM‐13 cells. Together, these results demonstrate that 10a is a new POLRMT inhibitor, which may provide a candidate lead for AML treatment.

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.