1. Pixantrone as a novel MCM2 inhibitor for ovarian cancer treatment.
- Author
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Chen Q, Sun Y, Li H, Liu S, Zhang H, Cheng Z, and Wang Y
- Subjects
- Animals, Female, Humans, Mice, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, DNA Replication drug effects, Mice, Nude, Molecular Docking Simulation, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Isoquinolines pharmacology, Isoquinolines chemistry, Isoquinolines therapeutic use, Minichromosome Maintenance Complex Component 2 metabolism, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Ovarian Neoplasms metabolism
- Abstract
Background: Mini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation., Methods: Molecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo., Results: Pixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety., Conclusion: These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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