2. Academic Validation
  3. 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

  • Nat Commun. 2017 Jun 9;8:15772. doi: 10.1038/ncomms15772.
Elena Campaner 1 2,  Alessandra Rustighi 1,  Alessandro Zannini 1 2,  Alberto Cristiani 1,  Silvano Piazza 1,  Yari Ciani 1,  Ori Kalid 3,  Gali Golan 3,  Erkan Baloglu 3,  Sharon Shacham 3,  Barbara Valsasina 4,  Ulisse Cucchi 4,  Agnese Chiara Pippione 5,  Marco Lucio Lolli 5,  Barbara Giabbai 6,  Paola Storici 6,  Paolo Carloni 7,  Giulia Rossetti 7 8 9,  Federica Benvenuti 10,  Ezia Bello 11,  Maurizio D'Incalci 11,  Elisa Cappuzzello 12,  Antonio Rosato 12 13,  Giannino Del Sal 1 2
Affiliations

Affiliations

  • 1 National Laboratory CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
  • 2 Department of Life Sciences, University of Trieste, Trieste 34127, Italy.
  • 3 Karyopharm Therapeutics, Newton, Massachusetts 02459, USA.
  • 4 Nerviano Medical Sciences Srl, Nerviano 20014, Italy.
  • 5 Department of Science and Drug Technology, University of Torino, Torino 10125, Italy.
  • 6 Elettra Sincrotrone Trieste S.C.p.A., Area Science Park Basovizza, Trieste 34149, Italy.
  • 7 Computational Biomedicine, Institute for Advanced Simulation (IAS-5) and Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, Jülich 52425, Germany.
  • 8 Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, Jülich 52425, Germany.
  • 9 Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen 52074, Germany.
  • 10 International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park Padriciano, Trieste 34149, Italy.
  • 11 IRCCS-Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
  • 12 Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Padova 35128, Italy.
  • 13 Veneto Institute of Oncology (IOV)-IRCCS, Padova 35128, Italy.
PMID: 28598431 DOI: 10.1038/ncomms15772
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-123847
    ≥98.0%, PIN1 Inhibitor