Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines
The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdow...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (15), p.3469-3474 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3474 |
|---|---|
| container_issue | 15 |
| container_start_page | 3469 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 24 |
| creator | Cheeseman, Matthew D Faisal, Amir Rayter, Sydonia Barbeau, Olivier R Kalusa, Andrew Westlake, Maura Burke, Rosemary Swan, Michael van Montfort, Rob Linardopoulos, Spiros Jones, Keith |
| description | The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.067 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1551629299</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1551629299</sourcerecordid><originalsourceid>FETCH-LOGICAL-c406t-caef3de95bbbce3d61a3c61c5a328ede7584c4db04b188abf4f9d82b261e1d8c3</originalsourceid><addsrcrecordid>eNo9kDtPwzAUhS0EoqXwBxiQRwYSbMc2sZhQeUpFMIDEZtnOTePKeRCnSOXXk4rCdJdzPp37IXRKSUoJlZer1NYupIxQnhKREnm1h6aUS55knIh9NCVKkiRX_GOCjmJckTFIOD9EE8aVyIRSU9S_mX4Jg2-WeKgAv74-01vcVdC0w6aDa8wueGJ9NP0mDJU3322AiJ1ZR8CVX1ZhgyMEcIP_Amy6thva6CP2zY5k6i740kOBHYSQBN9APEYHpQkRTnZ3ht7v797mj8ni5eFpfrNIHCdySJyBMitACWutg6yQ1GROUidMxnIo4Erk3PHCEm5pnhtb8lIVObNMUqBF7rIZOv_ldn37uYY46NrH7QzTQLuOmgpBJVNMqTHKfqOub2PsodRd7-vxaU2J3rrWK711rbeuNRF6dD2Wznb8ta2h-K_8yc1-AItlfZY</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1551629299</pqid></control><display><type>article</type><title>Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Cheeseman, Matthew D ; Faisal, Amir ; Rayter, Sydonia ; Barbeau, Olivier R ; Kalusa, Andrew ; Westlake, Maura ; Burke, Rosemary ; Swan, Michael ; van Montfort, Rob ; Linardopoulos, Spiros ; Jones, Keith</creator><creatorcontrib>Cheeseman, Matthew D ; Faisal, Amir ; Rayter, Sydonia ; Barbeau, Olivier R ; Kalusa, Andrew ; Westlake, Maura ; Burke, Rosemary ; Swan, Michael ; van Montfort, Rob ; Linardopoulos, Spiros ; Jones, Keith</creatorcontrib><description>The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.05.067</identifier><identifier>PMID: 24953599</identifier><language>eng</language><publisher>England</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Phenotype ; Phosphoprotein Phosphatases - antagonists & inhibitors ; Phosphoprotein Phosphatases - metabolism ; Protein Phosphatase 2C ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacology ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-08, Vol.24 (15), p.3469-3474</ispartof><rights>Copyright © 2014. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-caef3de95bbbce3d61a3c61c5a328ede7584c4db04b188abf4f9d82b261e1d8c3</citedby><cites>FETCH-LOGICAL-c406t-caef3de95bbbce3d61a3c61c5a328ede7584c4db04b188abf4f9d82b261e1d8c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24953599$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheeseman, Matthew D</creatorcontrib><creatorcontrib>Faisal, Amir</creatorcontrib><creatorcontrib>Rayter, Sydonia</creatorcontrib><creatorcontrib>Barbeau, Olivier R</creatorcontrib><creatorcontrib>Kalusa, Andrew</creatorcontrib><creatorcontrib>Westlake, Maura</creatorcontrib><creatorcontrib>Burke, Rosemary</creatorcontrib><creatorcontrib>Swan, Michael</creatorcontrib><creatorcontrib>van Montfort, Rob</creatorcontrib><creatorcontrib>Linardopoulos, Spiros</creatorcontrib><creatorcontrib>Jones, Keith</creatorcontrib><title>Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Phenotype</subject><subject>Phosphoprotein Phosphatases - antagonists & inhibitors</subject><subject>Phosphoprotein Phosphatases - metabolism</subject><subject>Protein Phosphatase 2C</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kDtPwzAUhS0EoqXwBxiQRwYSbMc2sZhQeUpFMIDEZtnOTePKeRCnSOXXk4rCdJdzPp37IXRKSUoJlZer1NYupIxQnhKREnm1h6aUS55knIh9NCVKkiRX_GOCjmJckTFIOD9EE8aVyIRSU9S_mX4Jg2-WeKgAv74-01vcVdC0w6aDa8wueGJ9NP0mDJU3322AiJ1ZR8CVX1ZhgyMEcIP_Amy6thva6CP2zY5k6i740kOBHYSQBN9APEYHpQkRTnZ3ht7v797mj8ni5eFpfrNIHCdySJyBMitACWutg6yQ1GROUidMxnIo4Erk3PHCEm5pnhtb8lIVObNMUqBF7rIZOv_ldn37uYY46NrH7QzTQLuOmgpBJVNMqTHKfqOub2PsodRd7-vxaU2J3rrWK711rbeuNRF6dD2Wznb8ta2h-K_8yc1-AItlfZY</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Cheeseman, Matthew D</creator><creator>Faisal, Amir</creator><creator>Rayter, Sydonia</creator><creator>Barbeau, Olivier R</creator><creator>Kalusa, Andrew</creator><creator>Westlake, Maura</creator><creator>Burke, Rosemary</creator><creator>Swan, Michael</creator><creator>van Montfort, Rob</creator><creator>Linardopoulos, Spiros</creator><creator>Jones, Keith</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140801</creationdate><title>Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines</title><author>Cheeseman, Matthew D ; Faisal, Amir ; Rayter, Sydonia ; Barbeau, Olivier R ; Kalusa, Andrew ; Westlake, Maura ; Burke, Rosemary ; Swan, Michael ; van Montfort, Rob ; Linardopoulos, Spiros ; Jones, Keith</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-caef3de95bbbce3d61a3c61c5a328ede7584c4db04b188abf4f9d82b261e1d8c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Phenotype</topic><topic>Phosphoprotein Phosphatases - antagonists & inhibitors</topic><topic>Phosphoprotein Phosphatases - metabolism</topic><topic>Protein Phosphatase 2C</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheeseman, Matthew D</creatorcontrib><creatorcontrib>Faisal, Amir</creatorcontrib><creatorcontrib>Rayter, Sydonia</creatorcontrib><creatorcontrib>Barbeau, Olivier R</creatorcontrib><creatorcontrib>Kalusa, Andrew</creatorcontrib><creatorcontrib>Westlake, Maura</creatorcontrib><creatorcontrib>Burke, Rosemary</creatorcontrib><creatorcontrib>Swan, Michael</creatorcontrib><creatorcontrib>van Montfort, Rob</creatorcontrib><creatorcontrib>Linardopoulos, Spiros</creatorcontrib><creatorcontrib>Jones, Keith</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheeseman, Matthew D</au><au>Faisal, Amir</au><au>Rayter, Sydonia</au><au>Barbeau, Olivier R</au><au>Kalusa, Andrew</au><au>Westlake, Maura</au><au>Burke, Rosemary</au><au>Swan, Michael</au><au>van Montfort, Rob</au><au>Linardopoulos, Spiros</au><au>Jones, Keith</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>24</volume><issue>15</issue><spage>3469</spage><epage>3474</epage><pages>3469-3474</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms.</abstract><cop>England</cop><pmid>24953599</pmid><doi>10.1016/j.bmcl.2014.05.067</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2014-08, Vol.24 (15), p.3469-3474 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1551629299 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Discovery Drug Screening Assays, Antitumor Humans Molecular Structure Phenotype Phosphoprotein Phosphatases - antagonists & inhibitors Phosphoprotein Phosphatases - metabolism Protein Phosphatase 2C Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology Tumor Suppressor Protein p53 - metabolism |
| title | Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T21%3A57%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20the%20PPM1D%20phenotype;%202,4-bisarylthiazoles%20cause%20highly%20selective%20apoptosis%20in%20PPM1D%20amplified%20cell-lines&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Cheeseman,%20Matthew%20D&rft.date=2014-08-01&rft.volume=24&rft.issue=15&rft.spage=3469&rft.epage=3474&rft.pages=3469-3474&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2014.05.067&rft_dat=%3Cproquest_cross%3E1551629299%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1551629299&rft_id=info:pmid/24953599&rfr_iscdi=true |