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Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression
Univ Zurich, Switzerland.
Univ Zurich, Switzerland.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 1335Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 1335
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-154554DOI: 10.1038/s41598-019-38579-7ISI: 000457616300223PubMedID: 30718768OAI: oai:DiVA.org:liu-154554DiVA, id: diva2:1290517
Note

Funding Agencies|Promedica-Stiftung-UBS; Stiftung fur Krebsbekampfung and Stiftung fur wissenschaftliche Forschung of the University of Zurich; Swiss National Science Foundation; Forschungskredit of the University of Zurich; AIRC [IG 14180]; University of Padua [COZZ_SID18_01]; Swedish Society for Medical Research (SSMF); Swedish Research Council (VR); Linkoping University (LiU); H2020-MSCA-RISE network 3D-NEONET; foundation Jeanssons Stiftelser; Magnus Bergvall Foundation

Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-03-26

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