New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery
MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI<sub>50</sub> values 13.52-31.04 μM) and CC<sub>50 Wi-38</sub> = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (<i>K</i> <sub>D</sub> = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.
Authors
- Tommaso Felicetti (ORCID: https://orcid.org/0000-0001-9369-8564)
- Maria Agnese Della Fazia (ORCID: https://orcid.org/0000-0002-5373-8477)
- Oriana Tabarrini (ORCID: https://orcid.org/0000-0003-2693-5675)
- Martina Pacetti (ORCID: https://orcid.org/0009-0000-3638-8500)
- Maria Letizia Barreca (ORCID: https://orcid.org/0000-0003-3530-5042)
- Jialing Yu (ORCID: https://orcid.org/0000-0002-9615-157X)
- Nicola Di-Iacovo
- Giuseppe Manfroni (ORCID: https://orcid.org/0000-0003-0207-3927)
- Mariangela Morlando (ORCID: https://orcid.org/0000-0002-8327-4423)
- Danilo Piobbico (ORCID: https://orcid.org/0000-0003-4240-1526)
- Yves Pommier (ORCID: https://orcid.org/0000-0002-3108-0758)
- Violetta Cecchetti (ORCID: https://orcid.org/0000-0001-8558-7004)
- Yilun Sun (ORCID: https://orcid.org/0000-0002-6249-2704)
- Stefania Pieroni (ORCID: https://orcid.org/0000-0003-3910-503X)
- Serena Massari (ORCID: https://orcid.org/0000-0002-9992-6318)
- Stefano Sabatini (ORCID: https://orcid.org/0000-0003-0971-3536)
- Giuseppe Servillo (ORCID: https://orcid.org/0000-0001-7960-7689)
- Fei Wang (ORCID: https://orcid.org/0000-0001-9961-0543)
Institutions
- Chinese Academy of Sciences (CN)
- University of Perugia (IT)
- Center for Cancer Research (US)
- Chengdu Institute of Biology (CN)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1039/d4md00649f
- Citations
- 5
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Dipartimenti di Eccellenza
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Sapienza Università di Roma
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro