2. Academic Validation
  3. Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase

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

  • J Med Chem. 2023 Apr 13;66(7):5118-5153. doi: 10.1021/acs.jmedchem.3c00058.
Xinnan Li 1,  Xiaotong Ze 1,  Shengnan Zhou 1,  Zhaoxin Hu 1,  Chen He 1,  Yilin Jia 1,  Lihua Liu 1,  Tao Wang 1,  Junda Li 1,  Shengtao Xu 1,  Dong-Hua Yang 2,  Zhe-Sheng Chen 3,  Hequan Yao 1,  Jinyi Xu 1,  Hong Yao 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 2 New York College of Traditional Chinese Medicine, 200 Old Country Road, Mineola, New York 11501, United States.
  • 3 College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, United States.
PMID: 36997840 DOI: 10.1021/acs.jmedchem.3c00058
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.

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