2. Academic Validation
  3. Micafungin: A promising inhibitor of UBE2M in cancer cell growth suppression

Micafungin: A promising inhibitor of UBE2M in cancer cell growth suppression

  • Eur J Med Chem. 2023 Nov 15:260:115732. doi: 10.1016/j.ejmech.2023.115732.
M A A Mamun 1,  Shuan Liu 1,  Lijie Zhao 1,  Lijuan Zhao 2,  Zhong-Rui Li 1,  Dandan Shen 3,  Yu Zheng 1,  Yi-Chao Zheng 4,  Hong-Min Liu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; XNA platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China.
  • 2 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; XNA platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China.
  • 3 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Laboratory of Endometrial Disease Prevention and Treatment Zhengzhou China, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 4 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; XNA platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 5 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; XNA platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China. Electronic address: [email protected].
PMID: 37651876 DOI: 10.1016/j.ejmech.2023.115732
Abstract

Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) Enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation Enzymes that play a vital role in this pathway. Studies have shown that targeting UBE2M in Cancer treatment is crucial, as it regulates many molecular mechanisms like DNA damage, Apoptosis, and cell proliferation. However, developing small molecule inhibitors against UBE2M remains challenging due to the lack of suitable druggable pockets. We have discovered that Micafungin, an Antifungal agent that inhibits the production of 1,3-β-D-glucan in Fungal cell walls, acts as a neddylation inhibitor that targets UBE2M. Biochemical studies reveal that Micafungin obstructs neddylation and stabilizes UBE2M. In cellular experiments, the drug was found to interact with UBE2M, prevent neddylation, accumulate cullin ring ligases (CRLs) substrates, reduce cell survival and migration, and induce DNA damage in gastric Cancer cells. This research uncovers a new anti-cancer mechanism for Micafungin, paving the way for the development of a novel class of neddylation inhibitors that target UBE2M.

Keywords

Drug repurposing; E2 conjugating enzyme; Micafungin; Neddylation; UBE2M.

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