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Molecules. 2019 Mar 19;24(6). pii: E1073. doi: 10.3390/molecules24061073.

Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells.

Author information

1
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. ntth@skku.edu.
2
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. honguyenanhminh@gmail.com.
3
Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA. sbl.kmkim@gmail.com.
4
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. sipoppy@hanmail.net.
5
Chemistry, Faculty of Engineering & Physical Sciences, University of Southampton, Highfield, Southampton SO17 1BJ, UK. P.Mizar@soton.ac.uk.
6
Chemistry, Faculty of Engineering & Physical Sciences, University of Southampton, Highfield, Southampton SO17 1BJ, UK. jwe1g13@soton.ac.uk.
7
Chemistry, Faculty of Engineering & Physical Sciences, University of Southampton, Highfield, Southampton SO17 1BJ, UK. S.S.Lee@soton.ac.uk.
8
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. kyeongkyu@skku.edu.

Abstract

Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.

KEYWORDS:

deubiquitinase; inhibitor; protein-protein interaction; ubiquitin; ubiquitination

PMID:
30893775
PMCID:
PMC6471062
DOI:
10.3390/molecules24061073
[Indexed for MEDLINE]
Free PMC Article

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