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 Bello, Maurizio D’Incalci, Elisa Cappuzzello, Antonio Rosato and Giannino Del Sal ()
Additional contact information
Elena Campaner: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Alessandra Rustighi: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Alessandro Zannini: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Alberto Cristiani: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Silvano Piazza: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Yari Ciani: National Laboratory CIB (LNCIB), Area Science Park Padriciano
Ori Kalid: Karyopharm Therapeutics
Gali Golan: Karyopharm Therapeutics
Erkan Baloglu: Karyopharm Therapeutics
Sharon Shacham: Karyopharm Therapeutics
Barbara Valsasina: Nerviano Medical Sciences Srl
Ulisse Cucchi: Nerviano Medical Sciences Srl
Agnese Chiara Pippione: University of Torino
Marco Lucio Lolli: University of Torino
Barbara Giabbai: Elettra Sincrotrone Trieste S.C.p.A., Area Science Park Basovizza
Paola Storici: Elettra Sincrotrone Trieste S.C.p.A., Area Science Park Basovizza
Paolo Carloni: Computational Biomedicine, Institute for Advanced Simulation (IAS-5) and Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich
Giulia Rossetti: Computational Biomedicine, Institute for Advanced Simulation (IAS-5) and Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich
Federica Benvenuti: International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park Padriciano
Ezia Bello: IRCCS-Mario Negri Institute for Pharmacological Research
Maurizio D’Incalci: IRCCS-Mario Negri Institute for Pharmacological Research
Elisa Cappuzzello: Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova
Antonio Rosato: Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova
Giannino Del Sal: National Laboratory CIB (LNCIB), Area Science Park Padriciano

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15772

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