Peptidyl-prolyl cis–trans isomerase, NIMA-interacting 1 (PIN1) is a peptidyl-prolyl isomerase that binds phospho-Ser/Thr-Pro motifs in proteins and catalyzes the cis–trans isomerization of proline peptide bonds. PIN1 is overexpressed in several cancers including high-grade serous ovarian cancer. Since few therapies are effective against this cancer, PIN1 could be a therapeutic target but effective PIN1 inhibitors are lacking. To identify molecules with in vivo inhibitory effects on PIN1, we used consensus docking to model existing PIN1-ligand X-ray structures and to screen a chemical database for candidate inhibitors. Ten molecules were selected and tested in cellular assays, leading to the identification of VS10 that bound and inhibited PIN1. VS10 treatment reduced the viability of ovarian cancer cell lines by inducing proteasomal PIN1 degradation, without effects on PIN1 transcription, and also reduced the levels of downstream targets β-catenin, cyclin D1, and pSer473-Akt. VS10 is a selective PIN1 inhibitor that may offer new opportunities for treating PIN1-overexpressing tumors.

Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects

Poli G.;Granchi C.;Tuccinardi T.;
2019-01-01

Abstract

Peptidyl-prolyl cis–trans isomerase, NIMA-interacting 1 (PIN1) is a peptidyl-prolyl isomerase that binds phospho-Ser/Thr-Pro motifs in proteins and catalyzes the cis–trans isomerization of proline peptide bonds. PIN1 is overexpressed in several cancers including high-grade serous ovarian cancer. Since few therapies are effective against this cancer, PIN1 could be a therapeutic target but effective PIN1 inhibitors are lacking. To identify molecules with in vivo inhibitory effects on PIN1, we used consensus docking to model existing PIN1-ligand X-ray structures and to screen a chemical database for candidate inhibitors. Ten molecules were selected and tested in cellular assays, leading to the identification of VS10 that bound and inhibited PIN1. VS10 treatment reduced the viability of ovarian cancer cell lines by inducing proteasomal PIN1 degradation, without effects on PIN1 transcription, and also reduced the levels of downstream targets β-catenin, cyclin D1, and pSer473-Akt. VS10 is a selective PIN1 inhibitor that may offer new opportunities for treating PIN1-overexpressing tumors.
2019
Russo Spena, C.; De Stefano, L.; Poli, G.; Granchi, C.; El Boustani, M.; Ecca, F.; Grassi, G.; Grassi, M.; Canzonieri, V.; Giordano, A.; Tuccinardi, T.; Caligiuri, I.; Rizzolio, F.
File in questo prodotto:
File Dimensione Formato  
2019_15.pdf

solo utenti autorizzati

Descrizione: reprint
Tipologia: Versione finale editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 1.33 MB
Formato Adobe PDF
1.33 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/997681
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 17
social impact