Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases
Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethyny...
Gespeichert in:
| Veröffentlicht in: | PloS one 2011, Vol.6 (6), p.e20789 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 6 |
| container_start_page | e20789 |
| container_title | PloS one |
| container_volume | 6 |
| creator | Klein, Michael Morillas, Montse Vendrell, Alexandre Brive, Lars Gebbia, Marinella Wallace, Iain M Giaever, Guri Nislow, Corey Posas, Francesc Grøtli, Morten |
| description | Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases. |
| doi_str_mv | 10.1371/journal.pone.0020789 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1304811923</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A476887833</galeid><doaj_id>oai_doaj_org_article_fabcaef0d2ff41cc830a52fe3aca7d2f</doaj_id><sourcerecordid>A476887833</sourcerecordid><originalsourceid>FETCH-LOGICAL-c672t-77ec2c0294546cbf3531301f7eeed5564a2801268cafe30b7803337d3aa9011f3</originalsourceid><addsrcrecordid>eNp1Ul2L1DAULaK46-o_EC34omDHfPQjfVlY1q-FBV_0OdymN23GTlKTdmX89WZmusMOKCU0vTnn3JPbkyQvKVlRXtEPazd7C8NqdBZXhDBSifpRck5rzrKSEf74wf4seRbCmpCCi7J8mpwxWtaCEnqe9B8xmM6-T8PWTn3chxRsm6oePKgJvfkDk3E2dTqFtDddP2xT1BrVZO4wNbY3jZmcT3VcEO24Lgtog9kfv4XwLv1pLAQMz5MnGoaAL5b3RfLj86fv11-z229fbq6vbjNVVmzKqgoVU4TVeZGXqtG84JQTqitEbIuizIEJQlkpFGjkpKkE4ZxXLQeoCaWaXySvD7rj4IJchhRkFMkFpTXjEXFzQLQO1nL0ZgN-Kx0YuS8430nwk1EDSg2NAtSkZVrnVCnBCRQsNgYFVSxGreygFX7jODcnat08yljqZhlQ0vgbijriLxd3c7PBVqGdPAwntNMTa3rZuTvJKa0Ez6MAPQioMCvpUaFXMO2Jx4_dinFgkVTwkkXOm6Wpd79mDNN_xrKgOog3N1a7aEBtTFDyKq9KIWL_HWr1D1R8WtwYFaOoTayfEPLFsHcheNTHy1Iid0G-NyN3QZZLkCPt1cNBHUn3yeV_AYx28g4</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1304811923</pqid></control><display><type>article</type><title>Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases</title><source>Public Library of Science (PLoS) Journals Open Access</source><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Recercat</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SWEPUB Freely available online</source><source>Free Full-Text Journals in Chemistry</source><creator>Klein, Michael ; Morillas, Montse ; Vendrell, Alexandre ; Brive, Lars ; Gebbia, Marinella ; Wallace, Iain M ; Giaever, Guri ; Nislow, Corey ; Posas, Francesc ; Grøtli, Morten</creator><creatorcontrib>Klein, Michael ; Morillas, Montse ; Vendrell, Alexandre ; Brive, Lars ; Gebbia, Marinella ; Wallace, Iain M ; Giaever, Guri ; Nislow, Corey ; Posas, Francesc ; Grøtli, Morten</creatorcontrib><description>Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0020789</identifier><identifier>PMID: 21698101</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine ; Andra medicinska och farmaceutiska grundvetenskaper ; Bioinformatics ; Biology ; Cell Cycle ; Chemical Sciences ; Chemical synthesis ; Chemistry ; Drug Design ; Drug dosages ; Enzyme inhibitors ; Gene Expression ; Genomes ; Genètica ; Hog1 protein ; Inhibitors ; Inhibitory Concentration 50 ; Kemi ; Kinases ; Magnetic Resonance Spectroscopy ; Mutagenesis ; Other Basic Medicine ; Pharmaceutical sciences ; Phosphotransferases ; Protein biosynthesis ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein-serine/threonine kinase ; Proteins ; Proteïnes quinases ; Selectivity ; Signal transduction ; Signaling ; Technology assessment ; Threonine ; Yeast ; Yeasts</subject><ispartof>PloS one, 2011, Vol.6 (6), p.e20789</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Klein et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2011 Klein et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited info:eu-repo/semantics/openAccess</rights><rights>Klein et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c672t-77ec2c0294546cbf3531301f7eeed5564a2801268cafe30b7803337d3aa9011f3</citedby><cites>FETCH-LOGICAL-c672t-77ec2c0294546cbf3531301f7eeed5564a2801268cafe30b7803337d3aa9011f3</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/PMC3117834/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117834/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,4010,23845,26951,27900,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21698101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://gup.ub.gu.se/publication/162059$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Klein, Michael</creatorcontrib><creatorcontrib>Morillas, Montse</creatorcontrib><creatorcontrib>Vendrell, Alexandre</creatorcontrib><creatorcontrib>Brive, Lars</creatorcontrib><creatorcontrib>Gebbia, Marinella</creatorcontrib><creatorcontrib>Wallace, Iain M</creatorcontrib><creatorcontrib>Giaever, Guri</creatorcontrib><creatorcontrib>Nislow, Corey</creatorcontrib><creatorcontrib>Posas, Francesc</creatorcontrib><creatorcontrib>Grøtli, Morten</creatorcontrib><title>Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases.</description><subject>Adenosine</subject><subject>Andra medicinska och farmaceutiska grundvetenskaper</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Cell Cycle</subject><subject>Chemical Sciences</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Drug Design</subject><subject>Drug dosages</subject><subject>Enzyme inhibitors</subject><subject>Gene Expression</subject><subject>Genomes</subject><subject>Genètica</subject><subject>Hog1 protein</subject><subject>Inhibitors</subject><subject>Inhibitory Concentration 50</subject><subject>Kemi</subject><subject>Kinases</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mutagenesis</subject><subject>Other Basic Medicine</subject><subject>Pharmaceutical sciences</subject><subject>Phosphotransferases</subject><subject>Protein biosynthesis</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-serine/threonine kinase</subject><subject>Proteins</subject><subject>Proteïnes quinases</subject><subject>Selectivity</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Technology assessment</subject><subject>Threonine</subject><subject>Yeast</subject><subject>Yeasts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>XX2</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ul2L1DAULaK46-o_EC34omDHfPQjfVlY1q-FBV_0OdymN23GTlKTdmX89WZmusMOKCU0vTnn3JPbkyQvKVlRXtEPazd7C8NqdBZXhDBSifpRck5rzrKSEf74wf4seRbCmpCCi7J8mpwxWtaCEnqe9B8xmM6-T8PWTn3chxRsm6oePKgJvfkDk3E2dTqFtDddP2xT1BrVZO4wNbY3jZmcT3VcEO24Lgtog9kfv4XwLv1pLAQMz5MnGoaAL5b3RfLj86fv11-z229fbq6vbjNVVmzKqgoVU4TVeZGXqtG84JQTqitEbIuizIEJQlkpFGjkpKkE4ZxXLQeoCaWaXySvD7rj4IJchhRkFMkFpTXjEXFzQLQO1nL0ZgN-Kx0YuS8430nwk1EDSg2NAtSkZVrnVCnBCRQsNgYFVSxGreygFX7jODcnat08yljqZhlQ0vgbijriLxd3c7PBVqGdPAwntNMTa3rZuTvJKa0Ez6MAPQioMCvpUaFXMO2Jx4_dinFgkVTwkkXOm6Wpd79mDNN_xrKgOog3N1a7aEBtTFDyKq9KIWL_HWr1D1R8WtwYFaOoTayfEPLFsHcheNTHy1Iid0G-NyN3QZZLkCPt1cNBHUn3yeV_AYx28g4</recordid><startdate>2011</startdate><enddate>2011</enddate><creator>Klein, Michael</creator><creator>Morillas, Montse</creator><creator>Vendrell, Alexandre</creator><creator>Brive, Lars</creator><creator>Gebbia, Marinella</creator><creator>Wallace, Iain M</creator><creator>Giaever, Guri</creator><creator>Nislow, Corey</creator><creator>Posas, Francesc</creator><creator>Grøtli, Morten</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>XX2</scope><scope>5PM</scope><scope>AAOVB</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>F1U</scope><scope>ZZAVC</scope><scope>DOA</scope></search><sort><creationdate>2011</creationdate><title>Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases</title><author>Klein, Michael ; Morillas, Montse ; Vendrell, Alexandre ; Brive, Lars ; Gebbia, Marinella ; Wallace, Iain M ; Giaever, Guri ; Nislow, Corey ; Posas, Francesc ; Grøtli, Morten</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c672t-77ec2c0294546cbf3531301f7eeed5564a2801268cafe30b7803337d3aa9011f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenosine</topic><topic>Andra medicinska och farmaceutiska grundvetenskaper</topic><topic>Bioinformatics</topic><topic>Biology</topic><topic>Cell Cycle</topic><topic>Chemical Sciences</topic><topic>Chemical synthesis</topic><topic>Chemistry</topic><topic>Drug Design</topic><topic>Drug dosages</topic><topic>Enzyme inhibitors</topic><topic>Gene Expression</topic><topic>Genomes</topic><topic>Genètica</topic><topic>Hog1 protein</topic><topic>Inhibitors</topic><topic>Inhibitory Concentration 50</topic><topic>Kemi</topic><topic>Kinases</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Mutagenesis</topic><topic>Other Basic Medicine</topic><topic>Pharmaceutical sciences</topic><topic>Phosphotransferases</topic><topic>Protein biosynthesis</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-serine/threonine kinase</topic><topic>Proteins</topic><topic>Proteïnes quinases</topic><topic>Selectivity</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Technology assessment</topic><topic>Threonine</topic><topic>Yeast</topic><topic>Yeasts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Klein, Michael</creatorcontrib><creatorcontrib>Morillas, Montse</creatorcontrib><creatorcontrib>Vendrell, Alexandre</creatorcontrib><creatorcontrib>Brive, Lars</creatorcontrib><creatorcontrib>Gebbia, Marinella</creatorcontrib><creatorcontrib>Wallace, Iain M</creatorcontrib><creatorcontrib>Giaever, Guri</creatorcontrib><creatorcontrib>Nislow, Corey</creatorcontrib><creatorcontrib>Posas, Francesc</creatorcontrib><creatorcontrib>Grøtli, Morten</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection (ProQuest)</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>Recercat</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SWEPUB Göteborgs universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Göteborgs universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Klein, Michael</au><au>Morillas, Montse</au><au>Vendrell, Alexandre</au><au>Brive, Lars</au><au>Gebbia, Marinella</au><au>Wallace, Iain M</au><au>Giaever, Guri</au><au>Nislow, Corey</au><au>Posas, Francesc</au><au>Grøtli, Morten</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e20789</spage><pages>e20789-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21698101</pmid><doi>10.1371/journal.pone.0020789</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011, Vol.6 (6), p.e20789 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1304811923 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Recercat; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Andra medicinska och farmaceutiska grundvetenskaper Bioinformatics Biology Cell Cycle Chemical Sciences Chemical synthesis Chemistry Drug Design Drug dosages Enzyme inhibitors Gene Expression Genomes Genètica Hog1 protein Inhibitors Inhibitory Concentration 50 Kemi Kinases Magnetic Resonance Spectroscopy Mutagenesis Other Basic Medicine Pharmaceutical sciences Phosphotransferases Protein biosynthesis Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-serine/threonine kinase Proteins Proteïnes quinases Selectivity Signal transduction Signaling Technology assessment Threonine Yeast Yeasts |
| title | Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T22%3A45%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Design,%20synthesis%20and%20characterization%20of%20a%20highly%20effective%20inhibitor%20for%20analog-sensitive%20(as)%20kinases&rft.jtitle=PloS%20one&rft.au=Klein,%20Michael&rft.date=2011&rft.volume=6&rft.issue=6&rft.spage=e20789&rft.pages=e20789-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0020789&rft_dat=%3Cgale_plos_%3EA476887833%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1304811923&rft_id=info:pmid/21698101&rft_galeid=A476887833&rft_doaj_id=oai_doaj_org_article_fabcaef0d2ff41cc830a52fe3aca7d2f&rfr_iscdi=true |