A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

Elena Campaner, Alessandra Rustighi, Alessandro Zannini, Alberto Cristiani, Silvano Piazza, Yari Ciani, Ori Kalid, Gali Golan, Erkan Baloglu, Sharon Shacham, Barbara Valsasina, Ulisse Cucchi, Agnese Chiara Pippione, Marco Lucio Lolli, Barbara Giabbai, Paola Storici, Paolo Carloni, Giulia Rossetti, Federica Benvenuti, Ezia BelloMaurizio D'Incalci, Elisa Cappuzzello, Antonio Rosato, Giannino Del Sal

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number15772
JournalNature Communications
Volume8
DOIs
Publication statusPublished - Jun 9 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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