Researchers Identify New Drug Candidate UR214-9 That Targets Septin Structures in Ovarian and Other Cancers
Researchers have identified that the small molecule UR214-9 disrupts septin protein complex assembly in ovarian cancer cells, impairing cell division, proliferation, and invasion. Septins are cytoskeletal proteins that form enigmatic higher-order structures in cancer cells, and septin-2 is overexpressed in epithelial ovarian cancer and associated with increased mortality. The findings suggest septins represent a druggable target across multiple cancer types, including ovarian, endometrial, breast, and pancreatic cancers.
A new preprint study published on bioRxiv reports that the small molecule UR214-9, an analog of forchlorfenuron (FCF), disrupts the assembly of septin hetero-octamers in ovarian cancer cells, converting normal septin complexes into aberrant higher-order aggregates and filamentous structures. The researchers first established that septin-2 is overexpressed in epithelial ovarian cancer (EOC) and correlates with increased patient mortality, selecting SKOV-3 ovarian cancer cells as a model system to recreate and study these structures in vitro. Mechanistically, UR214-9 prevents the proper incorporation of SEPT2, SEPT7, and SEPT9 into canonical octameric complexes, producing assembly-defective oligomers that reorganize into noodle-like filaments, perinuclear rings, and web-like nuclear networks. These structural disruptions impaired cytokinesis, cell proliferation, adhesion, invasion, and migration in cancer cells, while leaving ceramide transport and ER/Golgi structure largely intact, suggesting a degree of selectivity. In animal xenograft models, UR214-9 reduced tumor growth across ovarian, endometrial, and breast cancer models, and global transcriptomic analysis indicated limited off-target effects. Treated animals showed no significant observable toxicity, supporting the compound's potential safety profile. The study also introduces a new in vitro platform for recreating and studying aberrant septin architectures, which had previously been difficult to model outside living cells.
What's missing
As a preprint, this study has not yet undergone peer review. Key limitations include the reliance on xenograft models rather than immunocompetent or patient-derived tumor models, and the transcriptomic off-target analysis was performed only in breast and pancreatic cancer cell lines rather than the primary ovarian cancer model. Pharmacokinetic and pharmacodynamic data for UR214-9 in vivo are not detailed, and the precise molecular binding mechanism of UR214-9 to septin subunits remains to be fully characterized. Long-term toxicity and selectivity across normal versus cancerous tissues also require further investigation.
What different sources said
- bioRxivCenter
Reconstruction of septin higher-order nano-size structures in ovarian cancer cells uncover susceptibility to the septin-targeting small molecule UR214-9
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