TY  - JOUR
AU  - Campaner, Elena
AU  - Rustighi, Alessandra
AU  - Zannini, Alessandro
AU  - Cristiani, Alberto
AU  - Piazza, Silvano
AU  - Ciani, Yari
AU  - Kalid, Ori
AU  - Golan, Gali
AU  - Baloglu, Erkan
AU  - Shacham, Sharon
AU  - Valsasina, Barbara
AU  - Cucchi, Ulisse
AU  - Pippione, Agnese Chiara
AU  - Lolli, Marco Lucio
AU  - Giabbai, Barbara
AU  - Storici, Paola
AU  - Carloni, Paolo
AU  - Rossetti, Giulia
AU  - Benvenuti, Federica
AU  - Bello, Ezia
AU  - D’Incalci, Maurizio
AU  - Cappuzzello, Elisa
AU  - Rosato, Antonio
AU  - Del Sal, Giannino
TI  - A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
JO  - Nature Communications
VL  - 8
SN  - 2041-1723
CY  - London
PB  - Nature Publishing Group
M1  - FZJ-2017-04535
SP  - 15772 -
PY  - 2017
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000402967000001
C6  - pmid:28598431
DO  - DOI:10.1038/ncomms15772
UR  - https://juser.fz-juelich.de/record/834627
ER  -