Dataset Information

Natural product target identification of wheldone as a KIF11 inhibitor in ovarian cancer using the DiffPOP (Differential Protein Precipitation) method

ABSTRACT: Wheldone, a fungal metabolite, was identified as a cytotoxic compound in high-grade serous ovarian cancer (HGSOC). Wheldone triggered caspase 3/7–dependent apoptosis and reduced migration, invasion, and spheroid growth. Wheldone was also capable of triggering apoptosis in chemoresistant HGSOC models. Wheldone caused significant downregulation of HNRNPD expression, 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, DiffPOP (differential precipitation of proteins), wheldone was found to act as an inhibitor of 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 analysis 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 four cell lines treated. Overall, wheldone represents a promising lead compound for targeting KIF11 in chemoresistant ovarian cancer, with future studies needed to improve its pharmacokinetics and delivery.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Dany Pechalrieu

LAB HEAD: Alexander Adibekian

PROVIDER: PXD070302 | Pride | 2026-05-25

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	240119_human_library_w_PO4.tsv	Tabular
	240121_OV231_DMSO_1_Slot1-28_1_3396.d.zip	Other
	240121_OV231_DMSO_1_Slot1-28_1_3402.d.zip	Other
	240121_OV231_DMSO_2_Slot1-30_1_3398.d.zip	Other
	240121_OV231_DMSO_2_Slot1-30_1_3404.d.zip	Other

Items per page:

1 - 5 of 52

Publications

Natural Product Target Identification of Wheldone, a Fungal Metabolite, as a KIF11 Inhibitor in Ovarian Cancer Using the DiffPOP (Differential Protein Precipitation) Method.

Khin Manead M Saldana Alejandra Cavazos AC Rangel-Grimaldo Manuel M Raja Huzefa A HA Abegg Daniel D Ekiert Julia J Liu Chang C Misra Sweta S Ratia Kiira K Adibekian Alexander A Gao Yu Y Kulp Samuel K SK Coss Christopher C CC Oberlies Nicholas H NH Burdette Joanna E JE

Molecular & cellular proteomics : MCP 20260323 5

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 cl ...[more]

PMID: 41881190

Similar Datasets

Project description:At the blastocyst stage, the embryo invades the uterine and the pluripotent epiblast cells get reshaped from an amorphous ball into a polarized cup-shaped epithelium. At the same time, the transiently established naïve pluripotency is dismantled, transforming into a more developmentally advanced post-implantation pluripotent state. The major driver of the differentiation process is the autocrine Fgf/Mek/Erk singling which promotes the exit of naïve pluripotency. However, inhibiting Mek alone is not sufficient to maintain the cells in the naïve state suggesting the contribution of additional, as yet unidentified, pro-differentiation signals. Using a 3D embryonic stem cells (ESC) based model of epiblast development we established an automated pipeline for cell culture and analysis and performed a large-scale functional screen to identify factors regulating the development of the pluripotent lineage. We found that the mitotic kinases – Aurora kinase A (Aurka) and Polo-like kinase (PLK) positively regulate Erk signalling in a Mek-independent manner. We determined that Aurka and Erk form a complex in ESCs and suppression of Aurka activity delays the exit of naïve pluripotency. Moreover, a combination of Aurka and Mek inhibition enabled the de novo derivation of ESC lines from mouse embryos. Interestingly, during cell division, we found that phospho-Erk (pErk) localizes on the spindle poles at prophase and metaphase, gradually decreasing its signal at anaphase and telophase. Proximity biotinylation analysis of the pErk interactome identified the formation of PLK/pErk complex in metaphase cells. Moreover, inhibition of PLK, but not Mek or Aurka, resulted in a substantial decrease in Erk phosphorylation at the mitotic spindle. In summary, our findings demonstrate that the pluripotent cells continuously generate and perceive two types of Erk-mediated pro-differentiation cues - autocrine signals of the Fgf/Mek cascade and cell-intrinsic cues via the mitotic kinase Aurka and PLK. Altogether, these signals promote the exit of naïve pluripotency, driving the transient pace of embryonic development.