TY - JOUR
T1 - Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects
AU - Russo Spena, Concetta
AU - De Stefano, Lucia
AU - Poli, Giulio
AU - Granchi, Carlotta
AU - El Boustani, Maguie
AU - Ecca, Fabrizio
AU - Grassi, Gabriele
AU - Grassi, Mario
AU - Canzonieri, Vincenzo
AU - Giordano, Antonio
AU - Tuccinardi, Tiziano
AU - Caligiuri, Isabella
AU - Rizzolio, Flavio
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - consensus docking
KW - ovarian cancer
KW - Pin1
KW - small molecule inhibitors
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U2 - 10.1002/jcp.28224
DO - 10.1002/jcp.28224
M3 - Article
AN - SCOPUS:85060764987
VL - 234
SP - 15708
EP - 15716
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 1097-4652
IS - 9
ER -