Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors
Isothiazolo[4,3- b ]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5- b ]pyridine scaffold was expl...
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| Veröffentlicht in: | Organic & biomolecular chemistry 2024-09, Vol.22 (36), p.7373-7389 |
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| container_title | Organic & biomolecular chemistry |
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| creator | Ivanova, Yulia Spittaels, Sander Gao, Ling-Jie Schols, Dominique Van Meervelt, Luc Froeyen, Mathy Dehaen, Wim De Jonghe, Steven |
| description | Isothiazolo[4,3-
b
]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-
b
]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-
b
]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-
b
]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
A novel route to various substituted isothiazolo[4,5-
b
]pyridines was established. The compounds completely lacked GAK affinity, which was explained by
in silico
analysis. |
| doi_str_mv | 10.1039/d4ob00908h |
| format | Article |
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b
]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-
b
]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-
b
]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-
b
]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
A novel route to various substituted isothiazolo[4,5-
b
]pyridines was established. The compounds completely lacked GAK affinity, which was explained by
in silico
analysis.</description><identifier>ISSN: 1477-0520</identifier><identifier>EISSN: 1477-0539</identifier><identifier>DOI: 10.1039/d4ob00908h</identifier><identifier>PMID: 39171941</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Binders ; Chemical synthesis ; Cyclin G ; Enzyme inhibitors ; Humans ; Inhibitors ; Intracellular Signaling Peptides and Proteins ; Kinases ; Models, Molecular ; Molecular modelling ; Molecular Structure ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - metabolism ; Pyridines ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacology</subject><ispartof>Organic & biomolecular chemistry, 2024-09, Vol.22 (36), p.7373-7389</ispartof><rights>Copyright Royal Society of Chemistry 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c229t-278a7f5b35074e7a66584f8cf1c5311c8b2a9d5f5200dc50b01af6898eece6a63</cites><orcidid>0000-0002-9597-0629 ; 0000-0002-3872-6558 ; 0000-0002-6131-5693 ; 0000-0002-8675-6540 ; 0000-0001-8889-3621</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39171941$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ivanova, Yulia</creatorcontrib><creatorcontrib>Spittaels, Sander</creatorcontrib><creatorcontrib>Gao, Ling-Jie</creatorcontrib><creatorcontrib>Schols, Dominique</creatorcontrib><creatorcontrib>Van Meervelt, Luc</creatorcontrib><creatorcontrib>Froeyen, Mathy</creatorcontrib><creatorcontrib>Dehaen, Wim</creatorcontrib><creatorcontrib>De Jonghe, Steven</creatorcontrib><title>Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors</title><title>Organic & biomolecular chemistry</title><addtitle>Org Biomol Chem</addtitle><description>Isothiazolo[4,3-
b
]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-
b
]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-
b
]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-
b
]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
A novel route to various substituted isothiazolo[4,5-
b
]pyridines was established. The compounds completely lacked GAK affinity, which was explained by
in silico
analysis.</description><subject>Binders</subject><subject>Chemical synthesis</subject><subject>Cyclin G</subject><subject>Enzyme inhibitors</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Kinases</subject><subject>Models, Molecular</subject><subject>Molecular modelling</subject><subject>Molecular Structure</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Pyridines</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkcFLwzAUh4Mobk4v3pWAFxWrSdMkzXFO3cTBDupJpKRpQjO3ZiatUP96q9N5eg_ex-_xvgfAIUaXGBFxVSQuR0igtNwCfZxwHiFKxPamj1EP7IUwRwgLzpJd0CMCcywS3Af6sa3qUgcboKwKqD_kopG1dRV0Btrg6tLKT7dwL8kFjV5XrbeFrXQHB6hatbAVHEcyBKesrHUB32wlg4an4-HDGbRVaXNbOx_2wY6Ri6APfusAPN_dPo0m0XQ2vh8Np5GKY1FHMU8lNzQnFPFEc8kYTROTKoMVJRirNI-lKKjpLkKFoihHWBqWilRrpZlkZABO1rkr794bHeps7hpfdSszghEjjMWUd9T5mlLeheC1yVbeLqVvM4yyb6PZTTK7_jE66eDj38gmX-pig_4p7ICjNeCD2kz_X0K-AHnSeo8</recordid><startdate>20240918</startdate><enddate>20240918</enddate><creator>Ivanova, Yulia</creator><creator>Spittaels, Sander</creator><creator>Gao, Ling-Jie</creator><creator>Schols, Dominique</creator><creator>Van Meervelt, Luc</creator><creator>Froeyen, Mathy</creator><creator>Dehaen, Wim</creator><creator>De Jonghe, Steven</creator><general>Royal Society of Chemistry</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>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0002-9597-0629</orcidid><orcidid>https://orcid.org/0000-0002-3872-6558</orcidid><orcidid>https://orcid.org/0000-0002-6131-5693</orcidid><orcidid>https://orcid.org/0000-0002-8675-6540</orcidid><orcidid>https://orcid.org/0000-0001-8889-3621</orcidid></search><sort><creationdate>20240918</creationdate><title>Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors</title><author>Ivanova, Yulia ; Spittaels, Sander ; Gao, Ling-Jie ; Schols, Dominique ; Van Meervelt, Luc ; Froeyen, Mathy ; Dehaen, Wim ; De Jonghe, Steven</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c229t-278a7f5b35074e7a66584f8cf1c5311c8b2a9d5f5200dc50b01af6898eece6a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Binders</topic><topic>Chemical synthesis</topic><topic>Cyclin G</topic><topic>Enzyme inhibitors</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Kinases</topic><topic>Models, Molecular</topic><topic>Molecular modelling</topic><topic>Molecular Structure</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Pyridines</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ivanova, Yulia</creatorcontrib><creatorcontrib>Spittaels, Sander</creatorcontrib><creatorcontrib>Gao, Ling-Jie</creatorcontrib><creatorcontrib>Schols, Dominique</creatorcontrib><creatorcontrib>Van Meervelt, Luc</creatorcontrib><creatorcontrib>Froeyen, Mathy</creatorcontrib><creatorcontrib>Dehaen, Wim</creatorcontrib><creatorcontrib>De Jonghe, Steven</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>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ivanova, Yulia</au><au>Spittaels, Sander</au><au>Gao, Ling-Jie</au><au>Schols, Dominique</au><au>Van Meervelt, Luc</au><au>Froeyen, Mathy</au><au>Dehaen, Wim</au><au>De Jonghe, Steven</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors</atitle><jtitle>Organic & biomolecular chemistry</jtitle><addtitle>Org Biomol Chem</addtitle><date>2024-09-18</date><risdate>2024</risdate><volume>22</volume><issue>36</issue><spage>7373</spage><epage>7389</epage><pages>7373-7389</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>Isothiazolo[4,3-
b
]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-
b
]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-
b
]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-
b
]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
A novel route to various substituted isothiazolo[4,5-
b
]pyridines was established. The compounds completely lacked GAK affinity, which was explained by
in silico
analysis.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>39171941</pmid><doi>10.1039/d4ob00908h</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-9597-0629</orcidid><orcidid>https://orcid.org/0000-0002-3872-6558</orcidid><orcidid>https://orcid.org/0000-0002-6131-5693</orcidid><orcidid>https://orcid.org/0000-0002-8675-6540</orcidid><orcidid>https://orcid.org/0000-0001-8889-3621</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| issn | 1477-0520 1477-0539 |
| language | eng |
| recordid | cdi_crossref_primary_10_1039_D4OB00908H |
| source | MEDLINE; Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| subjects | Binders Chemical synthesis Cyclin G Enzyme inhibitors Humans Inhibitors Intracellular Signaling Peptides and Proteins Kinases Models, Molecular Molecular modelling Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism Pyridines Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology |
| title | Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors |
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