Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects

Concetta Russo Spena, Lucia De Stefano, Giulio Poli, Carlotta Granchi, Maguie El Boustani, Fabrizio Ecca, Gabriele Grassi, Mario Grassi, Vincenzo Canzonieri, Antonio Giordano, Tiziano Tuccinardi, Isabella Caligiuri, Flavio Rizzolio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)15708-15716
Number of pages9
JournalJournal of Cellular Physiology
Volume234
Issue number9
DOIs
Publication statusPublished - Sep 2019

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Keywords

  • consensus docking
  • ovarian cancer
  • Pin1
  • small molecule inhibitors

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

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. (2019). Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects. Journal of Cellular Physiology, 234(9), 15708-15716. https://doi.org/10.1002/jcp.28224