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

Abstract

High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound D26, which exerted a strong antiproliferative effect on several cancer cells and decreased mitochondrial-related genes expression. In addition, mechanism studies demonstrated that D26 arrested cell cycle at the G1 phase and had no effect on apoptosis, depolarized mitochondria, or reactive oxidative stress generation in A2780 cells. Importantly, D26 exhibited more potent anticancer activity than the lead IMT1B in A2780 xenograft nude mice and had no observable toxic effect. All results suggest that D26 deserves to be further investigated as a potent and safe antitumor candidate.

Identification of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer

“…All the synthesized compounds were assessed for their POLRMT inhibitory activity through the combined evaluation including mitochondria coded ubiquinone oxidoreductase core subunit 1 (ND1) transcript inhibition level and cell proliferation assays . The MIA PaCa-2 cell line, one of PC cell lines, was selected for evaluation as its exhibition of high sensitivity to POLRMT inhibitors .…”

“…However, further optimization is necessary to enhance its antipancreatic cancer activity. In our previous studies, the initial exploration of the structure–activity relationship (SAR) for IMT1B has been conducted, with an emphasis on the discovery of novel molecular scaffolds through the application of scaffold hopping strategies . Replacement of the coumarin scaffold with structures such as naphthalene and indole led to a significant reduction or even elimination of its activity, indicating the pivotal role played by the coumarin core in maintaining its functionality.…”

“…In our previous studies, the initial exploration of the structure−activity relationship (SAR) for IMT1B has been conducted, with an emphasis on the discovery of novel molecular scaffolds through the application of scaffold hopping strategies. 33 Replacement of the coumarin scaffold with structures such as naphthalene and indole led to a significant reduction or even elimination of its activity, indicating the pivotal role played by the coumarin core in maintaining its functionality. However, the chemical space surrounding the coumarin core remains unexplored, which necessitates urgent investigations of diverse substitutions on the coumarin core to elucidate their impact on antipancreatic cancer activity.…”

Mitochondria transcription and cancer

“…Importantly, IMT1 exhibits broad-spectrum anti-tumor effects without significant side effects in vivo [ 84 ]. Li et al optimized the structure of IMT1 and obtained more potent derivatives with enhanced anti-tumor activity both in vitro and in vivo [ 85 ]. Wang et al developed a mitochondrial protease targeting chimera (MtPTAC) by linking the POLRMT-targeting inhibitor IMT1 with the mitochondrial protease ClpP.…”

Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

“…Second, cancer cells commonly favor enhanced glycolysis, but OXPHOS can also be upregulated in certain cancers [122,123]. OXPHOS upregulation seems to be limited to some cancer subtypes, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma, endometrial cancer, ovarian cancer [123], the chemotherapyresistant cancer stem cell subpopulation [124], and slow-cycling tumor cells [125]. Therefore, OXPHOS inhibition is considered to be an effective therapeutic approach for cancer cells that favor energy production by mitochondrial OXPHOS over glycolysis [122,123].…”