Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 and TYK2. The development of small-molecule inhibitors that are selective for a s...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2018-06, Vol.61 (12), p.5235-5244 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 5244 |
|---|---|
| container_issue | 12 |
| container_start_page | 5235 |
| container_title | Journal of medicinal chemistry |
| container_volume | 61 |
| creator | Grimster, Neil P Anderson, Erica Alimzhanov, Marat Bebernitz, Geraldine Bell, Kirsten Chuaqui, Claudio Deegan, Tracy Ferguson, Andrew D Gero, Thomas Harsch, Andreas Huszar, Dennis Kawatkar, Aarti Kettle, Jason G Lyne, Paul Read, Jon A Rivard Costa, Caroline Ruston, Linette Schroeder, Patricia Shi, Jie Su, Qibin Throner, Scott Toader, Dorin Vasbinder, Melissa Woessner, Richard Wang, Haixia Wu, Allan Ye, Minwei Zheng, Weijia Zinda, Michael |
| description | Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition). |
| doi_str_mv | 10.1021/acs.jmedchem.8b00076 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2049558190</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2049558190</sourcerecordid><originalsourceid>FETCH-LOGICAL-a348t-efea6a14c3d2c9ac8e79f6caddfac5319e513bf55981fd40c6e2ac9573e1f37e3</originalsourceid><addsrcrecordid>eNp9kEtPAjEQxxujEUS_gTE9elnsY7uPI8EHCJGDGo-bbncqJfvAdpcEP71FwKOnSWZ-_5nMD6FrSoaUMHonlRuuKijUEqphkhNC4ugE9algJAgTEp6iPiGMBSxivIcunFt5hFPGz1GPpYmIIir66OPeONVswG6xrAu8WLemMt-yNU2NG40lfvHDEr-CNeB2nYn5XJZb3yhBtWYD-Hk0o3hmaukAT-ulyU3bWHeJzrQsHVwd6gC9Pz68jSfBfPE0HY_mgeRh0gagQUaShooXTKVSJRCnOlKyKLRUgtMUBOW5FiJNqC5CoiJgUqUi5kA1j4EP0O1-79o2Xx24Nqv8Q1CWsoamcxkjYSpEQlPi0XCPKts4Z0Fna2sqabcZJdlOaeaVZkel2UGpj90cLnS5n_2Fjg49QPbAb7zpbO0f_n_nD5y2hn8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2049558190</pqid></control><display><type>article</type><title>Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors</title><source>ACS Publications</source><creator>Grimster, Neil P ; Anderson, Erica ; Alimzhanov, Marat ; Bebernitz, Geraldine ; Bell, Kirsten ; Chuaqui, Claudio ; Deegan, Tracy ; Ferguson, Andrew D ; Gero, Thomas ; Harsch, Andreas ; Huszar, Dennis ; Kawatkar, Aarti ; Kettle, Jason G ; Lyne, Paul ; Read, Jon A ; Rivard Costa, Caroline ; Ruston, Linette ; Schroeder, Patricia ; Shi, Jie ; Su, Qibin ; Throner, Scott ; Toader, Dorin ; Vasbinder, Melissa ; Woessner, Richard ; Wang, Haixia ; Wu, Allan ; Ye, Minwei ; Zheng, Weijia ; Zinda, Michael</creator><creatorcontrib>Grimster, Neil P ; Anderson, Erica ; Alimzhanov, Marat ; Bebernitz, Geraldine ; Bell, Kirsten ; Chuaqui, Claudio ; Deegan, Tracy ; Ferguson, Andrew D ; Gero, Thomas ; Harsch, Andreas ; Huszar, Dennis ; Kawatkar, Aarti ; Kettle, Jason G ; Lyne, Paul ; Read, Jon A ; Rivard Costa, Caroline ; Ruston, Linette ; Schroeder, Patricia ; Shi, Jie ; Su, Qibin ; Throner, Scott ; Toader, Dorin ; Vasbinder, Melissa ; Woessner, Richard ; Wang, Haixia ; Wu, Allan ; Ye, Minwei ; Zheng, Weijia ; Zinda, Michael</creatorcontrib><description>Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.8b00076</identifier><identifier>PMID: 29856615</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><ispartof>Journal of medicinal chemistry, 2018-06, Vol.61 (12), p.5235-5244</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-efea6a14c3d2c9ac8e79f6caddfac5319e513bf55981fd40c6e2ac9573e1f37e3</citedby><cites>FETCH-LOGICAL-a348t-efea6a14c3d2c9ac8e79f6caddfac5319e513bf55981fd40c6e2ac9573e1f37e3</cites><orcidid>0000-0003-0088-1250 ; 0000-0001-6330-5280</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b00076$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00076$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29856615$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grimster, Neil P</creatorcontrib><creatorcontrib>Anderson, Erica</creatorcontrib><creatorcontrib>Alimzhanov, Marat</creatorcontrib><creatorcontrib>Bebernitz, Geraldine</creatorcontrib><creatorcontrib>Bell, Kirsten</creatorcontrib><creatorcontrib>Chuaqui, Claudio</creatorcontrib><creatorcontrib>Deegan, Tracy</creatorcontrib><creatorcontrib>Ferguson, Andrew D</creatorcontrib><creatorcontrib>Gero, Thomas</creatorcontrib><creatorcontrib>Harsch, Andreas</creatorcontrib><creatorcontrib>Huszar, Dennis</creatorcontrib><creatorcontrib>Kawatkar, Aarti</creatorcontrib><creatorcontrib>Kettle, Jason G</creatorcontrib><creatorcontrib>Lyne, Paul</creatorcontrib><creatorcontrib>Read, Jon A</creatorcontrib><creatorcontrib>Rivard Costa, Caroline</creatorcontrib><creatorcontrib>Ruston, Linette</creatorcontrib><creatorcontrib>Schroeder, Patricia</creatorcontrib><creatorcontrib>Shi, Jie</creatorcontrib><creatorcontrib>Su, Qibin</creatorcontrib><creatorcontrib>Throner, Scott</creatorcontrib><creatorcontrib>Toader, Dorin</creatorcontrib><creatorcontrib>Vasbinder, Melissa</creatorcontrib><creatorcontrib>Woessner, Richard</creatorcontrib><creatorcontrib>Wang, Haixia</creatorcontrib><creatorcontrib>Wu, Allan</creatorcontrib><creatorcontrib>Ye, Minwei</creatorcontrib><creatorcontrib>Zheng, Weijia</creatorcontrib><creatorcontrib>Zinda, Michael</creatorcontrib><title>Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).</description><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kEtPAjEQxxujEUS_gTE9elnsY7uPI8EHCJGDGo-bbncqJfvAdpcEP71FwKOnSWZ-_5nMD6FrSoaUMHonlRuuKijUEqphkhNC4ugE9algJAgTEp6iPiGMBSxivIcunFt5hFPGz1GPpYmIIir66OPeONVswG6xrAu8WLemMt-yNU2NG40lfvHDEr-CNeB2nYn5XJZb3yhBtWYD-Hk0o3hmaukAT-ulyU3bWHeJzrQsHVwd6gC9Pz68jSfBfPE0HY_mgeRh0gagQUaShooXTKVSJRCnOlKyKLRUgtMUBOW5FiJNqC5CoiJgUqUi5kA1j4EP0O1-79o2Xx24Nqv8Q1CWsoamcxkjYSpEQlPi0XCPKts4Z0Fna2sqabcZJdlOaeaVZkel2UGpj90cLnS5n_2Fjg49QPbAb7zpbO0f_n_nD5y2hn8</recordid><startdate>20180628</startdate><enddate>20180628</enddate><creator>Grimster, Neil P</creator><creator>Anderson, Erica</creator><creator>Alimzhanov, Marat</creator><creator>Bebernitz, Geraldine</creator><creator>Bell, Kirsten</creator><creator>Chuaqui, Claudio</creator><creator>Deegan, Tracy</creator><creator>Ferguson, Andrew D</creator><creator>Gero, Thomas</creator><creator>Harsch, Andreas</creator><creator>Huszar, Dennis</creator><creator>Kawatkar, Aarti</creator><creator>Kettle, Jason G</creator><creator>Lyne, Paul</creator><creator>Read, Jon A</creator><creator>Rivard Costa, Caroline</creator><creator>Ruston, Linette</creator><creator>Schroeder, Patricia</creator><creator>Shi, Jie</creator><creator>Su, Qibin</creator><creator>Throner, Scott</creator><creator>Toader, Dorin</creator><creator>Vasbinder, Melissa</creator><creator>Woessner, Richard</creator><creator>Wang, Haixia</creator><creator>Wu, Allan</creator><creator>Ye, Minwei</creator><creator>Zheng, Weijia</creator><creator>Zinda, Michael</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0088-1250</orcidid><orcidid>https://orcid.org/0000-0001-6330-5280</orcidid></search><sort><creationdate>20180628</creationdate><title>Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors</title><author>Grimster, Neil P ; Anderson, Erica ; Alimzhanov, Marat ; Bebernitz, Geraldine ; Bell, Kirsten ; Chuaqui, Claudio ; Deegan, Tracy ; Ferguson, Andrew D ; Gero, Thomas ; Harsch, Andreas ; Huszar, Dennis ; Kawatkar, Aarti ; Kettle, Jason G ; Lyne, Paul ; Read, Jon A ; Rivard Costa, Caroline ; Ruston, Linette ; Schroeder, Patricia ; Shi, Jie ; Su, Qibin ; Throner, Scott ; Toader, Dorin ; Vasbinder, Melissa ; Woessner, Richard ; Wang, Haixia ; Wu, Allan ; Ye, Minwei ; Zheng, Weijia ; Zinda, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-efea6a14c3d2c9ac8e79f6caddfac5319e513bf55981fd40c6e2ac9573e1f37e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grimster, Neil P</creatorcontrib><creatorcontrib>Anderson, Erica</creatorcontrib><creatorcontrib>Alimzhanov, Marat</creatorcontrib><creatorcontrib>Bebernitz, Geraldine</creatorcontrib><creatorcontrib>Bell, Kirsten</creatorcontrib><creatorcontrib>Chuaqui, Claudio</creatorcontrib><creatorcontrib>Deegan, Tracy</creatorcontrib><creatorcontrib>Ferguson, Andrew D</creatorcontrib><creatorcontrib>Gero, Thomas</creatorcontrib><creatorcontrib>Harsch, Andreas</creatorcontrib><creatorcontrib>Huszar, Dennis</creatorcontrib><creatorcontrib>Kawatkar, Aarti</creatorcontrib><creatorcontrib>Kettle, Jason G</creatorcontrib><creatorcontrib>Lyne, Paul</creatorcontrib><creatorcontrib>Read, Jon A</creatorcontrib><creatorcontrib>Rivard Costa, Caroline</creatorcontrib><creatorcontrib>Ruston, Linette</creatorcontrib><creatorcontrib>Schroeder, Patricia</creatorcontrib><creatorcontrib>Shi, Jie</creatorcontrib><creatorcontrib>Su, Qibin</creatorcontrib><creatorcontrib>Throner, Scott</creatorcontrib><creatorcontrib>Toader, Dorin</creatorcontrib><creatorcontrib>Vasbinder, Melissa</creatorcontrib><creatorcontrib>Woessner, Richard</creatorcontrib><creatorcontrib>Wang, Haixia</creatorcontrib><creatorcontrib>Wu, Allan</creatorcontrib><creatorcontrib>Ye, Minwei</creatorcontrib><creatorcontrib>Zheng, Weijia</creatorcontrib><creatorcontrib>Zinda, Michael</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grimster, Neil P</au><au>Anderson, Erica</au><au>Alimzhanov, Marat</au><au>Bebernitz, Geraldine</au><au>Bell, Kirsten</au><au>Chuaqui, Claudio</au><au>Deegan, Tracy</au><au>Ferguson, Andrew D</au><au>Gero, Thomas</au><au>Harsch, Andreas</au><au>Huszar, Dennis</au><au>Kawatkar, Aarti</au><au>Kettle, Jason G</au><au>Lyne, Paul</au><au>Read, Jon A</au><au>Rivard Costa, Caroline</au><au>Ruston, Linette</au><au>Schroeder, Patricia</au><au>Shi, Jie</au><au>Su, Qibin</au><au>Throner, Scott</au><au>Toader, Dorin</au><au>Vasbinder, Melissa</au><au>Woessner, Richard</au><au>Wang, Haixia</au><au>Wu, Allan</au><au>Ye, Minwei</au><au>Zheng, Weijia</au><au>Zinda, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2018-06-28</date><risdate>2018</risdate><volume>61</volume><issue>12</issue><spage>5235</spage><epage>5244</epage><pages>5235-5244</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>29856615</pmid><doi>10.1021/acs.jmedchem.8b00076</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-0088-1250</orcidid><orcidid>https://orcid.org/0000-0001-6330-5280</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2018-06, Vol.61 (12), p.5235-5244 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2049558190 |
| source | ACS Publications |
| title | Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T03%3A15%3A03IST&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=Discovery%20and%20Optimization%20of%20a%20Novel%20Series%20of%20Highly%20Selective%20JAK1%20Kinase%20Inhibitors&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Grimster,%20Neil%20P&rft.date=2018-06-28&rft.volume=61&rft.issue=12&rft.spage=5235&rft.epage=5244&rft.pages=5235-5244&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.8b00076&rft_dat=%3Cproquest_cross%3E2049558190%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=2049558190&rft_id=info:pmid/29856615&rfr_iscdi=true |