Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects
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. Sin...
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| Veröffentlicht in: | Journal of cellular physiology 2019-09, Vol.234 (9), p.15708-15716 |
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| container_title | Journal of cellular physiology |
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| creator | Russo Spena, Concetta De Stefano, Lucia Poli, Giulio Granchi, Carlotta El Boustani, Maguie Ecca, Fabrizio Grassi, Gabriele Grassi, Mario Canzonieri, Vincenzo Giordano, Antonio Tuccinardi, Tiziano Caligiuri, Isabella Rizzolio, Flavio |
| description | 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.
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. Here we developed a new inhibitor (VS10) that could offer new opportunities for treating PIN1‐overexpressing tumors. |
| doi_str_mv | 10.1002/jcp.28224 |
| format | Article |
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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. Here we developed a new inhibitor (VS10) that could offer new opportunities for treating PIN1‐overexpressing tumors.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.28224</identifier><identifier>PMID: 30697729</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>AKT protein ; Cancer ; consensus docking ; Cyclin D1 ; Docking ; Inhibitors ; Isomerization ; Organic chemistry ; Ovarian cancer ; Peptidylprolyl isomerase ; Pin1 ; Pin1 protein ; Proline ; Proteasomes ; small molecule inhibitors ; Therapeutic applications ; Transcription ; Tumor cell lines ; Tumors ; Viability</subject><ispartof>Journal of cellular physiology, 2019-09, Vol.234 (9), p.15708-15716</ispartof><rights>2019 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3884-536c2f4972e09b501315ea37df4d271dc55f63a26ac8aa33a7a917722746dc4a3</citedby><cites>FETCH-LOGICAL-c3884-536c2f4972e09b501315ea37df4d271dc55f63a26ac8aa33a7a917722746dc4a3</cites><orcidid>0000-0002-3400-4363 ; 0000-0003-4353-5390</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.28224$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.28224$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30697729$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Russo Spena, Concetta</creatorcontrib><creatorcontrib>De Stefano, Lucia</creatorcontrib><creatorcontrib>Poli, Giulio</creatorcontrib><creatorcontrib>Granchi, Carlotta</creatorcontrib><creatorcontrib>El Boustani, Maguie</creatorcontrib><creatorcontrib>Ecca, Fabrizio</creatorcontrib><creatorcontrib>Grassi, Gabriele</creatorcontrib><creatorcontrib>Grassi, Mario</creatorcontrib><creatorcontrib>Canzonieri, Vincenzo</creatorcontrib><creatorcontrib>Giordano, Antonio</creatorcontrib><creatorcontrib>Tuccinardi, Tiziano</creatorcontrib><creatorcontrib>Caligiuri, Isabella</creatorcontrib><creatorcontrib>Rizzolio, Flavio</creatorcontrib><title>Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>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.
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. Here we developed a new inhibitor (VS10) that could offer new opportunities for treating PIN1‐overexpressing tumors.</description><subject>AKT protein</subject><subject>Cancer</subject><subject>consensus docking</subject><subject>Cyclin D1</subject><subject>Docking</subject><subject>Inhibitors</subject><subject>Isomerization</subject><subject>Organic chemistry</subject><subject>Ovarian cancer</subject><subject>Peptidylprolyl isomerase</subject><subject>Pin1</subject><subject>Pin1 protein</subject><subject>Proline</subject><subject>Proteasomes</subject><subject>small molecule inhibitors</subject><subject>Therapeutic applications</subject><subject>Transcription</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Viability</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp10D1PwzAQBmALgaB8DPwBZIkFhlB_xHE8oopPIegArNbVuYCrNCl2AuLfYygwIDHdcI9e3b2E7HN2whkT47lbnohSiHyNjDgzOssLJdbJKO14ZlTOt8h2jHPGmDFSbpItyQqjtTAj8vjoQz9AQ6MLiK1vn6ivsO197TFSoNOrW059--xnvu8CffP9M112MfpZgxSS614heGipg9ZhoFjX6Pq4SzZqaCLufc8d8nB-dj-5zG7uLq4mpzeZk2WZZ0oWTtS50QKZmSnGJVcIUld1XgnNK6dUXUgQBbgSQErQYHg6XOi8qFwOcoccrXKXoXsZMPZ24aPDpoEWuyFawbVRiSuV6OEfOu-G0KbrrBDClIpJzZM6XikX0pcBa7sMfgHh3XJmP8u2qWz7VXayB9-Jw2yB1a_8aTeB8Qq8-Qbf_0-y15PpKvIDAIKHhg</recordid><startdate>201909</startdate><enddate>201909</enddate><creator>Russo Spena, Concetta</creator><creator>De Stefano, Lucia</creator><creator>Poli, Giulio</creator><creator>Granchi, Carlotta</creator><creator>El Boustani, Maguie</creator><creator>Ecca, Fabrizio</creator><creator>Grassi, Gabriele</creator><creator>Grassi, Mario</creator><creator>Canzonieri, Vincenzo</creator><creator>Giordano, Antonio</creator><creator>Tuccinardi, Tiziano</creator><creator>Caligiuri, Isabella</creator><creator>Rizzolio, Flavio</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3400-4363</orcidid><orcidid>https://orcid.org/0000-0003-4353-5390</orcidid></search><sort><creationdate>201909</creationdate><title>Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects</title><author>Russo Spena, Concetta ; De Stefano, Lucia ; Poli, Giulio ; Granchi, Carlotta ; El Boustani, Maguie ; Ecca, Fabrizio ; Grassi, Gabriele ; Grassi, Mario ; Canzonieri, Vincenzo ; Giordano, Antonio ; Tuccinardi, Tiziano ; Caligiuri, Isabella ; Rizzolio, Flavio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3884-536c2f4972e09b501315ea37df4d271dc55f63a26ac8aa33a7a917722746dc4a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>AKT protein</topic><topic>Cancer</topic><topic>consensus docking</topic><topic>Cyclin D1</topic><topic>Docking</topic><topic>Inhibitors</topic><topic>Isomerization</topic><topic>Organic chemistry</topic><topic>Ovarian cancer</topic><topic>Peptidylprolyl isomerase</topic><topic>Pin1</topic><topic>Pin1 protein</topic><topic>Proline</topic><topic>Proteasomes</topic><topic>small molecule inhibitors</topic><topic>Therapeutic applications</topic><topic>Transcription</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><topic>Viability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Russo Spena, Concetta</creatorcontrib><creatorcontrib>De Stefano, Lucia</creatorcontrib><creatorcontrib>Poli, Giulio</creatorcontrib><creatorcontrib>Granchi, Carlotta</creatorcontrib><creatorcontrib>El Boustani, Maguie</creatorcontrib><creatorcontrib>Ecca, Fabrizio</creatorcontrib><creatorcontrib>Grassi, Gabriele</creatorcontrib><creatorcontrib>Grassi, Mario</creatorcontrib><creatorcontrib>Canzonieri, Vincenzo</creatorcontrib><creatorcontrib>Giordano, Antonio</creatorcontrib><creatorcontrib>Tuccinardi, Tiziano</creatorcontrib><creatorcontrib>Caligiuri, Isabella</creatorcontrib><creatorcontrib>Rizzolio, Flavio</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Russo Spena, Concetta</au><au>De Stefano, Lucia</au><au>Poli, Giulio</au><au>Granchi, Carlotta</au><au>El Boustani, Maguie</au><au>Ecca, Fabrizio</au><au>Grassi, Gabriele</au><au>Grassi, Mario</au><au>Canzonieri, Vincenzo</au><au>Giordano, Antonio</au><au>Tuccinardi, Tiziano</au><au>Caligiuri, Isabella</au><au>Rizzolio, Flavio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J Cell Physiol</addtitle><date>2019-09</date><risdate>2019</risdate><volume>234</volume><issue>9</issue><spage>15708</spage><epage>15716</epage><pages>15708-15716</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><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.
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. Here we developed a new inhibitor (VS10) that could offer new opportunities for treating PIN1‐overexpressing tumors.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30697729</pmid><doi>10.1002/jcp.28224</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-3400-4363</orcidid><orcidid>https://orcid.org/0000-0003-4353-5390</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | AKT protein Cancer consensus docking Cyclin D1 Docking Inhibitors Isomerization Organic chemistry Ovarian cancer Peptidylprolyl isomerase Pin1 Pin1 protein Proline Proteasomes small molecule inhibitors Therapeutic applications Transcription Tumor cell lines Tumors Viability |
| title | Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects |
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