PUBLICATION

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression

Authors
Kabakci, Z., Käppeli, S., Cantù, C., Jensen, L.D., König, C., Toggweiler, J., Gentili, C., Ribaudo, G., Zagotto, G., Basler, K., Pinna, L.A., Cozza, G., Ferrari, S.
ID
ZDB-PUB-190206-9
Date
2019
Source
Scientific Reports   9: 1335 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Adenomatous Polyposis Coli Protein/genetics
  • Animals
  • CDC2 Protein Kinase/genetics*
  • Cell Cycle/drug effects
  • Cell Cycle Checkpoints/genetics
  • Cell Division/genetics
  • Crystallography, X-Ray
  • Enzyme Inhibitors/pharmacology
  • Heterografts
  • Humans
  • Mice
  • Mitosis/genetics
  • Molecular Docking Simulation
  • Naphthoquinones/pharmacology
  • Neoplasms/genetics*
  • Neoplasms/pathology
  • Protein Conformation*
  • cdc25 Phosphatases/antagonists & inhibitors
  • cdc25 Phosphatases/chemistry
  • cdc25 Phosphatases/genetics*
  • cdc25 Phosphatases/ultrastructure
PubMed
30718768 Full text @ Sci. Rep.
Abstract
CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping