Related Experiment Video
Updated: May 22, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Natural Product Target Identification of Wheldone, a Fungal Metabolite, as a KIF11 Inhibitor in Ovarian Cancer Using
Manead Khin1, Alejandra Cavazos Saldana1, Manuel Rangel-Grimaldo2
1Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Abstract:
Wheldone, a fungal metabolite, was identified as a cytotoxic compound in high-grade serous ovarian cancer (HGSOC). Wheldone induced caspase 3/7-dependent apoptosis and reduced migration, invasion, and spheroid growth. Wheldone stimulated apoptosis in chemoresistant HGSOC models. Wheldone treatment caused significant downregulation of HNRNPD, a DNA repair protein, and increased DNA damage that could be blocked by N-acetyl-L-cysteine. In vivo, wheldone displayed minimal toxicity but was rapidly cleared from circulation, despite in vitro metabolic stability. Wheldone treatment in vivo did not demonstrate significant reduction in tumor burden. Therefore, in order to overcome these liabilities, it was necessary to find the protein target of wheldone so that modifications can be made to improve the drug-like characteristics of the compound. Using the drug-target interaction proteomics method, differential precipitation of proteins, wheldone was found to act as an inhibitor of Kinesin superfamily protein 11 (KIF11), a motor protein essential for mitotic spindle formation. An ATPase biochemical cell-free assay confirmed direct binding and functional inhibition of KIF11. Wheldone resulted in G2/M arrest and downstream regulation of mitotic proteins such as TPX2, AURKA, and phospho-histone H3. Proteomics after treatment of wheldone in four different HGSOC cancer cell lines all supported changes consistent with mitotic spindle assembly disruption. Further, KIF11 was one of only 13 proteins upregulated in all 4 cell lines treated. Overall, wheldone was found to be a fungal metabolite that inhibits KIF11 in chemoresistant ovarian cancer, with future studies needed to improve its pharmacokinetics and delivery.
Insights
Wheldone, a fungal compound, effectively kills ovarian cancer cells by inhibiting KIF11, a motor protein crucial for cell division. Further research aims to enhance its drug-like properties for improved cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- High-grade serous ovarian cancer (HGSOC) is a deadly disease with limited treatment options.
- Wheldone, a fungal metabolite, shows cytotoxic effects against HGSOC cells.
- Chemoresistance is a major challenge in HGSOC treatment.
Purpose of the Study:
- To identify the molecular target of wheldone to improve its drug-like characteristics.
- To investigate wheldone's mechanism of action in chemoresistant HGSOC models.
- To assess wheldone's potential as a therapeutic agent for ovarian cancer.
Main Methods:
- Differential precipitation of proteins (DiffPOP) was used to identify wheldone's protein target.
- Biochemical assays confirmed direct binding and inhibition of the target protein.
- Proteomics and cell cycle analysis were performed to study wheldone's effects on cancer cells.
Main Results:
- Wheldone was identified as an inhibitor of KIF11, a motor protein vital for mitotic spindle formation.
- Wheldone induced G2/M cell cycle arrest and apoptosis in HGSOC cells, including chemoresistant models.
- Treatment with wheldone led to disruption of mitotic spindle assembly and downregulation of DNA repair proteins.
Conclusions:
- Wheldone is a novel fungal metabolite that targets KIF11 in chemoresistant ovarian cancer.
- Wheldone demonstrates potential as an anti-cancer agent by inducing apoptosis and inhibiting cell proliferation.
- Further studies are required to optimize wheldone's pharmacokinetic properties and delivery for clinical application.
