This title appears in the Scientific Report :
2017
Please use the identifier:
http://dx.doi.org/10.1038/ncomms15772 in citations.
Please use the identifier: http://hdl.handle.net/2128/14863 in citations.
A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restore...
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Personal Name(s): | Campaner, Elena |
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Rustighi, Alessandra / Zannini, Alessandro / Cristiani, Alberto / Piazza, Silvano / Ciani, Yari / Kalid, Ori / Golan, Gali / Baloglu, Erkan / Shacham, Sharon / Valsasina, Barbara / Cucchi, Ulisse / Pippione, Agnese Chiara / Lolli, Marco Lucio / Giabbai, Barbara / Storici, Paola / Carloni, Paolo / Rossetti, Giulia / Benvenuti, Federica / Bello, Ezia / D’Incalci, Maurizio / Cappuzzello, Elisa / Rosato, Antonio / Del Sal, Giannino (Corresponding author) | |
Contributing Institute: |
Jülich Supercomputing Center; JSC Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5 |
Published in: | Nature Communications, 8 (2017) S. 15772 - |
Imprint: |
London
Nature Publishing Group
2017
|
DOI: |
10.1038/ncomms15772 |
PubMed ID: |
28598431 |
Document Type: |
Journal Article |
Research Program: |
Computational Science and Mathematical Methods |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/14863 in citations.
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo. |