A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct
MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. W...
Gespeichert in:
| Veröffentlicht in: | Oncotarget 2016-11, Vol.7 (44), p.71182-71197 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 71197 |
|---|---|
| container_issue | 44 |
| container_start_page | 71182 |
| container_title | Oncotarget |
| container_volume | 7 |
| creator | Ocasio, Cory A Rajasekaran, Mohan B Walker, Sarah Le Grand, Darren Spencer, John Pearl, Frances M G Ward, Simon E Savic, Velibor Pearl, Laurence H Hochegger, Helfrid Oliver, Antony W |
| description | MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors. |
| doi_str_mv | 10.18632/oncotarget.11511 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5342071</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1855789445</sourcerecordid><originalsourceid>FETCH-LOGICAL-c399t-430083baccec9a87803bdad0f3f6a1bec143e1efdd0b04e8eca05ecf5ffd91123</originalsourceid><addsrcrecordid>eNpVkcFOHDEMhqOKqiDKA3BBOXJgaTKZ7GQuSCtEaSWkXso58iTObmAmgSQD4jV4Yqbssl18sS3bn239hBxzds7VXFQ_YjCxQFpiOedccv6FHPC2bmeVlGJvJ94nRznfsclk3aiq_Ub2q0bOharmB-R1QZ1PudAlBkxQfAzUh5XvfImJRkdX4wCBXieE8gx9T-99gIxnFAN0PVravdBc0mjKmKCnECx1YzD_OFNqVpDAFEw-r9ETEOjggx_gA0VtHMAHamJYg76Trw76jEcbf0huf179vfw1u_lz_ftycTMzom3LrBaMKdGBMWhaUI1iorNgmRNuDrxDw2uBHJ21rGM1KjTAJBonnbMt55U4JBdr7sPYDWgNhjK9oB_SdFx60RG8_lwJfqWX8UlLUVes4RPgdANI8XHEXPTgs8G-h4BxzJorKRvV1rWcWvm61aSYc0K3XcOZfpdT_5dTv8s5zZzs3red-BBPvAHrdKS2</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1855789445</pqid></control><display><type>article</type><title>A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct</title><source>Freely Accessible Journals</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><creator>Ocasio, Cory A ; Rajasekaran, Mohan B ; Walker, Sarah ; Le Grand, Darren ; Spencer, John ; Pearl, Frances M G ; Ward, Simon E ; Savic, Velibor ; Pearl, Laurence H ; Hochegger, Helfrid ; Oliver, Antony W</creator><creatorcontrib>Ocasio, Cory A ; Rajasekaran, Mohan B ; Walker, Sarah ; Le Grand, Darren ; Spencer, John ; Pearl, Frances M G ; Ward, Simon E ; Savic, Velibor ; Pearl, Laurence H ; Hochegger, Helfrid ; Oliver, Antony W</creatorcontrib><description>MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.11511</identifier><identifier>PMID: 27563826</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Crystallization ; HeLa Cells ; Humans ; Microtubule-Associated Proteins - antagonists & inhibitors ; Microtubule-Associated Proteins - chemistry ; Phosphorylation ; Protein Domains ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - chemistry ; Research Paper ; Structure-Activity Relationship</subject><ispartof>Oncotarget, 2016-11, Vol.7 (44), p.71182-71197</ispartof><rights>Copyright: © 2016 Ocasio et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c399t-430083baccec9a87803bdad0f3f6a1bec143e1efdd0b04e8eca05ecf5ffd91123</citedby><cites>FETCH-LOGICAL-c399t-430083baccec9a87803bdad0f3f6a1bec143e1efdd0b04e8eca05ecf5ffd91123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342071/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342071/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27563826$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ocasio, Cory A</creatorcontrib><creatorcontrib>Rajasekaran, Mohan B</creatorcontrib><creatorcontrib>Walker, Sarah</creatorcontrib><creatorcontrib>Le Grand, Darren</creatorcontrib><creatorcontrib>Spencer, John</creatorcontrib><creatorcontrib>Pearl, Frances M G</creatorcontrib><creatorcontrib>Ward, Simon E</creatorcontrib><creatorcontrib>Savic, Velibor</creatorcontrib><creatorcontrib>Pearl, Laurence H</creatorcontrib><creatorcontrib>Hochegger, Helfrid</creatorcontrib><creatorcontrib>Oliver, Antony W</creatorcontrib><title>A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.</description><subject>Crystallization</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Microtubule-Associated Proteins - antagonists & inhibitors</subject><subject>Microtubule-Associated Proteins - chemistry</subject><subject>Phosphorylation</subject><subject>Protein Domains</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - chemistry</subject><subject>Research Paper</subject><subject>Structure-Activity Relationship</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFOHDEMhqOKqiDKA3BBOXJgaTKZ7GQuSCtEaSWkXso58iTObmAmgSQD4jV4Yqbssl18sS3bn239hBxzds7VXFQ_YjCxQFpiOedccv6FHPC2bmeVlGJvJ94nRznfsclk3aiq_Ub2q0bOharmB-R1QZ1PudAlBkxQfAzUh5XvfImJRkdX4wCBXieE8gx9T-99gIxnFAN0PVravdBc0mjKmKCnECx1YzD_OFNqVpDAFEw-r9ETEOjggx_gA0VtHMAHamJYg76Trw76jEcbf0huf179vfw1u_lz_ftycTMzom3LrBaMKdGBMWhaUI1iorNgmRNuDrxDw2uBHJ21rGM1KjTAJBonnbMt55U4JBdr7sPYDWgNhjK9oB_SdFx60RG8_lwJfqWX8UlLUVes4RPgdANI8XHEXPTgs8G-h4BxzJorKRvV1rWcWvm61aSYc0K3XcOZfpdT_5dTv8s5zZzs3red-BBPvAHrdKS2</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Ocasio, Cory A</creator><creator>Rajasekaran, Mohan B</creator><creator>Walker, Sarah</creator><creator>Le Grand, Darren</creator><creator>Spencer, John</creator><creator>Pearl, Frances M G</creator><creator>Ward, Simon E</creator><creator>Savic, Velibor</creator><creator>Pearl, Laurence H</creator><creator>Hochegger, Helfrid</creator><creator>Oliver, Antony W</creator><general>Impact Journals LLC</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161101</creationdate><title>A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct</title><author>Ocasio, Cory A ; Rajasekaran, Mohan B ; Walker, Sarah ; Le Grand, Darren ; Spencer, John ; Pearl, Frances M G ; Ward, Simon E ; Savic, Velibor ; Pearl, Laurence H ; Hochegger, Helfrid ; Oliver, Antony W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c399t-430083baccec9a87803bdad0f3f6a1bec143e1efdd0b04e8eca05ecf5ffd91123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Crystallization</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Microtubule-Associated Proteins - antagonists & inhibitors</topic><topic>Microtubule-Associated Proteins - chemistry</topic><topic>Phosphorylation</topic><topic>Protein Domains</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - chemistry</topic><topic>Research Paper</topic><topic>Structure-Activity Relationship</topic><toplevel>online_resources</toplevel><creatorcontrib>Ocasio, Cory A</creatorcontrib><creatorcontrib>Rajasekaran, Mohan B</creatorcontrib><creatorcontrib>Walker, Sarah</creatorcontrib><creatorcontrib>Le Grand, Darren</creatorcontrib><creatorcontrib>Spencer, John</creatorcontrib><creatorcontrib>Pearl, Frances M G</creatorcontrib><creatorcontrib>Ward, Simon E</creatorcontrib><creatorcontrib>Savic, Velibor</creatorcontrib><creatorcontrib>Pearl, Laurence H</creatorcontrib><creatorcontrib>Hochegger, Helfrid</creatorcontrib><creatorcontrib>Oliver, Antony W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ocasio, Cory A</au><au>Rajasekaran, Mohan B</au><au>Walker, Sarah</au><au>Le Grand, Darren</au><au>Spencer, John</au><au>Pearl, Frances M G</au><au>Ward, Simon E</au><au>Savic, Velibor</au><au>Pearl, Laurence H</au><au>Hochegger, Helfrid</au><au>Oliver, Antony W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>7</volume><issue>44</issue><spage>71182</spage><epage>71197</epage><pages>71182-71197</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>27563826</pmid><doi>10.18632/oncotarget.11511</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1949-2553 |
| ispartof | Oncotarget, 2016-11, Vol.7 (44), p.71182-71197 |
| issn | 1949-2553 1949-2553 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5342071 |
| source | Freely Accessible Journals; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access |
| subjects | Crystallization HeLa Cells Humans Microtubule-Associated Proteins - antagonists & inhibitors Microtubule-Associated Proteins - chemistry Phosphorylation Protein Domains Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - chemistry Research Paper Structure-Activity Relationship |
| title | A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T05%3A16%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20first%20generation%20inhibitor%20of%20human%20Greatwall%20kinase,%20enabled%20by%20structural%20and%20functional%20characterisation%20of%20a%20minimal%20kinase%20domain%20construct&rft.jtitle=Oncotarget&rft.au=Ocasio,%20Cory%20A&rft.date=2016-11-01&rft.volume=7&rft.issue=44&rft.spage=71182&rft.epage=71197&rft.pages=71182-71197&rft.issn=1949-2553&rft.eissn=1949-2553&rft_id=info:doi/10.18632/oncotarget.11511&rft_dat=%3Cproquest_pubme%3E1855789445%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1855789445&rft_id=info:pmid/27563826&rfr_iscdi=true |