Tozasertib Analogues as Inhibitors of Necroptotic Cell Death
Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspective...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-03, Vol.61 (5), p.1895-1920 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 61 |
| creator | Hofmans, Sam Devisscher, Lars Martens, Sofie Van Rompaey, Dries Goossens, Kenneth Divert, Tatyana Nerinckx, Wim Takahashi, Nozomi De Winter, Hans Van Der Veken, Pieter Goossens, Vera Vandenabeele, Peter Augustyns, Koen |
| description | Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model. |
| doi_str_mv | 10.1021/acs.jmedchem.7b01449 |
| format | Article |
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Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b01449</identifier><identifier>PMID: 29437386</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Aurora Kinase A - drug effects ; Aurora Kinase B - drug effects ; Cell Death - drug effects ; Mice ; Necrosis - prevention & control ; Piperazines - adverse effects ; Piperazines - chemistry ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors ; Systemic Inflammatory Response Syndrome - chemically induced ; Systemic Inflammatory Response Syndrome - drug therapy ; Tumor Necrosis Factor-alpha - adverse effects</subject><ispartof>Journal of medicinal chemistry, 2018-03, Vol.61 (5), p.1895-1920</ispartof><rights>Copyright © 2018 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-13dc376a4d6ed303ffa09cafa75e84a58ce598193d38d86e058ead718ce47a463</citedby><cites>FETCH-LOGICAL-a348t-13dc376a4d6ed303ffa09cafa75e84a58ce598193d38d86e058ead718ce47a463</cites><orcidid>0000-0002-8491-0073 ; 0000-0003-3779-6877 ; 0000-0002-5203-4339</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.7b01449$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01449$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29437386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hofmans, Sam</creatorcontrib><creatorcontrib>Devisscher, Lars</creatorcontrib><creatorcontrib>Martens, Sofie</creatorcontrib><creatorcontrib>Van Rompaey, Dries</creatorcontrib><creatorcontrib>Goossens, Kenneth</creatorcontrib><creatorcontrib>Divert, Tatyana</creatorcontrib><creatorcontrib>Nerinckx, Wim</creatorcontrib><creatorcontrib>Takahashi, Nozomi</creatorcontrib><creatorcontrib>De Winter, Hans</creatorcontrib><creatorcontrib>Van Der Veken, Pieter</creatorcontrib><creatorcontrib>Goossens, Vera</creatorcontrib><creatorcontrib>Vandenabeele, Peter</creatorcontrib><creatorcontrib>Augustyns, Koen</creatorcontrib><title>Tozasertib Analogues as Inhibitors of Necroptotic Cell Death</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.</description><subject>Animals</subject><subject>Aurora Kinase A - drug effects</subject><subject>Aurora Kinase B - drug effects</subject><subject>Cell Death - drug effects</subject><subject>Mice</subject><subject>Necrosis - prevention & control</subject><subject>Piperazines - adverse effects</subject><subject>Piperazines - chemistry</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Systemic Inflammatory Response Syndrome - chemically induced</subject><subject>Systemic Inflammatory Response Syndrome - drug therapy</subject><subject>Tumor Necrosis Factor-alpha - adverse effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9OwkAQhzdGI4i-gTH7AsXZP223iReCqCREL3huprtTKSmU7JaDPr2rgEdPk8z8vsnMx9itgLEAKe7RhvF6Q86uaDPOKxBaF2dsKFIJiTagz9kQQMpEZlIN2FUIawBQQqpLNpCFVrky2ZA9LLsvDOT7puKTLbbdx54Cx8Dn21VTNX3nA-9q_krWd7u-6xvLp9S2_JGwX12zixrbQDfHOmLvT7Pl9CVZvD3Pp5NFgkqbPhHKWZVnqF1GToGqa4TCYo15SkZjaiylhRGFcso4kxGkhtDlIvZ1jjpTI6YPe-MRIXiqy51vNug_SwHlj4wyyihPMsqjjIjdHbDdvoqzP-j0fQzAIfCLd3sfBYT_d34DJiButQ</recordid><startdate>20180308</startdate><enddate>20180308</enddate><creator>Hofmans, Sam</creator><creator>Devisscher, Lars</creator><creator>Martens, Sofie</creator><creator>Van Rompaey, Dries</creator><creator>Goossens, Kenneth</creator><creator>Divert, Tatyana</creator><creator>Nerinckx, Wim</creator><creator>Takahashi, Nozomi</creator><creator>De Winter, Hans</creator><creator>Van Der Veken, Pieter</creator><creator>Goossens, Vera</creator><creator>Vandenabeele, Peter</creator><creator>Augustyns, Koen</creator><general>American Chemical Society</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><orcidid>https://orcid.org/0000-0002-8491-0073</orcidid><orcidid>https://orcid.org/0000-0003-3779-6877</orcidid><orcidid>https://orcid.org/0000-0002-5203-4339</orcidid></search><sort><creationdate>20180308</creationdate><title>Tozasertib Analogues as Inhibitors of Necroptotic Cell Death</title><author>Hofmans, Sam ; Devisscher, Lars ; Martens, Sofie ; Van Rompaey, Dries ; Goossens, Kenneth ; Divert, Tatyana ; Nerinckx, Wim ; Takahashi, Nozomi ; De Winter, Hans ; Van Der Veken, Pieter ; Goossens, Vera ; Vandenabeele, Peter ; Augustyns, Koen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-13dc376a4d6ed303ffa09cafa75e84a58ce598193d38d86e058ead718ce47a463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Aurora Kinase A - drug effects</topic><topic>Aurora Kinase B - drug effects</topic><topic>Cell Death - drug effects</topic><topic>Mice</topic><topic>Necrosis - prevention & control</topic><topic>Piperazines - adverse effects</topic><topic>Piperazines - chemistry</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Systemic Inflammatory Response Syndrome - chemically induced</topic><topic>Systemic Inflammatory Response Syndrome - drug therapy</topic><topic>Tumor Necrosis Factor-alpha - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hofmans, Sam</creatorcontrib><creatorcontrib>Devisscher, Lars</creatorcontrib><creatorcontrib>Martens, Sofie</creatorcontrib><creatorcontrib>Van Rompaey, Dries</creatorcontrib><creatorcontrib>Goossens, Kenneth</creatorcontrib><creatorcontrib>Divert, Tatyana</creatorcontrib><creatorcontrib>Nerinckx, Wim</creatorcontrib><creatorcontrib>Takahashi, Nozomi</creatorcontrib><creatorcontrib>De Winter, Hans</creatorcontrib><creatorcontrib>Van Der Veken, Pieter</creatorcontrib><creatorcontrib>Goossens, Vera</creatorcontrib><creatorcontrib>Vandenabeele, Peter</creatorcontrib><creatorcontrib>Augustyns, Koen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hofmans, Sam</au><au>Devisscher, Lars</au><au>Martens, Sofie</au><au>Van Rompaey, Dries</au><au>Goossens, Kenneth</au><au>Divert, Tatyana</au><au>Nerinckx, Wim</au><au>Takahashi, Nozomi</au><au>De Winter, Hans</au><au>Van Der Veken, Pieter</au><au>Goossens, Vera</au><au>Vandenabeele, Peter</au><au>Augustyns, Koen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tozasertib Analogues as Inhibitors of Necroptotic Cell Death</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>29437386</pmid><doi>10.1021/acs.jmedchem.7b01449</doi><tpages>26</tpages><orcidid>https://orcid.org/0000-0002-8491-0073</orcidid><orcidid>https://orcid.org/0000-0003-3779-6877</orcidid><orcidid>https://orcid.org/0000-0002-5203-4339</orcidid></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2018-03, Vol.61 (5), p.1895-1920 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Aurora Kinase A - drug effects Aurora Kinase B - drug effects Cell Death - drug effects Mice Necrosis - prevention & control Piperazines - adverse effects Piperazines - chemistry Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors Systemic Inflammatory Response Syndrome - chemically induced Systemic Inflammatory Response Syndrome - drug therapy Tumor Necrosis Factor-alpha - adverse effects |
| title | Tozasertib Analogues as Inhibitors of Necroptotic Cell Death |
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