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

• Published in: European journal of medicinal chemistry Vol. 260; p. 115732
• Main Authors: Mamun, M.A.A., Liu, Shuan, Zhao, Lijie, Zhao, Lijuan, Li, Zhong-Rui, Shen, Dandan, Zheng, Yu, Zheng, Yi-Chao, Liu, Hong-Min
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 15.11.2023
• Subjects: Drug repurposing; E2 conjugating enzyme; Micafungin; Neddylation; UBE2M; Neddylation; Drug repurposing; Micafungin; E2 conjugating enzyme; UBE2M
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115732

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. [Display omitted] •New classes of neddylation inhibitors are discovered by HTRF-based drug screening.•Micafungin inhibits the neddylation of UBE2M by interacting with it.•Cancer cell proliferation and migration are prevented by Micafungin.•Through the upregulation of the NOXA, Micafungin causes apoptosis.