Selective miRNA network modulation by quinolone derivative CF5 is associated with potent anti-ovarian cancer activity.

Abstract

Ovarian cancer remains a leading cause of gynaecological cancer mortality, largely due to late diagnosis and limited options for recurrent disease. Dysregulation of microRNAs (miRNAs) contributes to tumour progression, highlighting the potential of pharmacological strategies that restore miRNA-mediated control. Here, we describe CF5, a fluoroquinolone derivative developed from enoxacin, the first-in-class small-molecule enhancer of miRNA processing (SMER), as a potent anticancer agent with a favourable selectivity profile. CF5 consistently inhibits proliferation and migration in ovarian cancer cells, restricts long-term clonogenic survival, and retains activity following TRBP knockdown, indicating reduced dependence on canonical SMER-associated pathways. Differential miRNA profiling identifies a CF5-associated miRNA expression pattern involving a discrete subset of upregulated miRNAs. Integrative bioinformatics and functional analyses reveal convergence on oncogenic regulatory processes, with downstream target genes including ALDOA, NACC1, VAV3, and PRRG4. Analysis of transcriptomic datasets shows that these genes are overexpressed in tumours and treatment with CF5 is able to restore levels to those found in healthy tissues. Together, these findings demonstrate that CF5 orchestrates targeted post-transcriptional regulatory networks involving proliferation, survival, metabolic and migratory programs. By combining enhanced biological activity with a distinct response to TRBP depletion, CF5 represents a new generation of miRNA-modulating compounds capable of exploiting molecular vulnerabilities in high-grade serous ovarian carcinoma. These results support further development of CF5 and related fluoroquinolone derivatives as promising therapeutics targeting post-transcriptional regulatory networks in ovarian cancer.

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