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000834627 1001_ $$0P:(DE-HGF)0$$aCampaner, Elena$$b0
000834627 245__ $$aA covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
000834627 260__ $$aLondon$$bNature Publishing Group$$c2017
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000834627 520__ $$aThe 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.
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000834627 7001_ $$0P:(DE-HGF)0$$aRustighi, Alessandra$$b1
000834627 7001_ $$0P:(DE-HGF)0$$aZannini, Alessandro$$b2
000834627 7001_ $$0P:(DE-HGF)0$$aCristiani, Alberto$$b3
000834627 7001_ $$0P:(DE-HGF)0$$aPiazza, Silvano$$b4
000834627 7001_ $$0P:(DE-HGF)0$$aCiani, Yari$$b5
000834627 7001_ $$0P:(DE-HGF)0$$aKalid, Ori$$b6
000834627 7001_ $$0P:(DE-HGF)0$$aGolan, Gali$$b7
000834627 7001_ $$0P:(DE-HGF)0$$aBaloglu, Erkan$$b8
000834627 7001_ $$0P:(DE-HGF)0$$aShacham, Sharon$$b9
000834627 7001_ $$0P:(DE-HGF)0$$aValsasina, Barbara$$b10
000834627 7001_ $$0P:(DE-HGF)0$$aCucchi, Ulisse$$b11
000834627 7001_ $$0P:(DE-HGF)0$$aPippione, Agnese Chiara$$b12
000834627 7001_ $$0P:(DE-HGF)0$$aLolli, Marco Lucio$$b13
000834627 7001_ $$0P:(DE-HGF)0$$aGiabbai, Barbara$$b14
000834627 7001_ $$00000-0002-2590-3332$$aStorici, Paola$$b15
000834627 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b16
000834627 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b17
000834627 7001_ $$0P:(DE-HGF)0$$aBenvenuti, Federica$$b18
000834627 7001_ $$0P:(DE-HGF)0$$aBello, Ezia$$b19
000834627 7001_ $$0P:(DE-HGF)0$$aD’Incalci, Maurizio$$b20
000834627 7001_ $$00000-0001-6733-795X$$aCappuzzello, Elisa$$b21
000834627 7001_ $$0P:(DE-HGF)0$$aRosato, Antonio$$b22
000834627 7001_ $$0P:(DE-HGF)0$$aDel Sal, Giannino$$b23$$eCorresponding author
000834627 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/ncomms15772$$gVol. 8, p. 15772 -$$p15772 -$$tNature Communications$$v8$$x2041-1723$$y2017
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