New aminopyrimidine derivatives as inhibitors of the TAM family
In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form...
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| Veröffentlicht in: | European journal of medicinal chemistry 2013-12, Vol.70, p.789-801 |
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| container_title | European journal of medicinal chemistry |
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| creator | Traoré, Ténin Cavagnino, Andrea Saettel, Nicolas Radvanyi, François Piguel, Sandrine Bernard-Pierrot, Isabelle Stoven, Véronique Legraverend, Michel |
| description | In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
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•Novel pyrimidine-based Met inhibitors were designed and synthesized.•They inhibited potently Met and Axl, as well as Tyro3 and Mer to a lesser extend.•Molecular modeling in Met (3F82 in pdb) and in a Tyro3 model suggested a type II inhibition. |
| doi_str_mv | 10.1016/j.ejmech.2013.10.037 |
| format | Article |
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[Display omitted]
•Novel pyrimidine-based Met inhibitors were designed and synthesized.•They inhibited potently Met and Axl, as well as Tyro3 and Mer to a lesser extend.•Molecular modeling in Met (3F82 in pdb) and in a Tyro3 model suggested a type II inhibition.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2013.10.037</identifier><identifier>PMID: 24239626</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Aminopyridines - chemical synthesis ; Aminopyridines - chemistry ; Aminopyridines - pharmacology ; Docking ; Dose-Response Relationship, Drug ; Humans ; Life Sciences ; Met inhibitors ; Models, Molecular ; Molecular modeling ; Molecular Structure ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-met - antagonists & inhibitors ; Proto-Oncogene Proteins c-met - metabolism ; Pyridones - chemical synthesis ; Pyridones - chemistry ; Pyridones - pharmacology ; Pyrimidine synthesis ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - metabolism ; Structure-Activity Relationship ; TAM inhibitors ; Type 2 inhibitors</subject><ispartof>European journal of medicinal chemistry, 2013-12, Vol.70, p.789-801</ispartof><rights>2013 Elsevier Masson SAS</rights><rights>Copyright © 2013 Elsevier Masson SAS. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-fa186431f9332578ee6eeea3a4f30b91298b150e6d1df3769c4bef8a4728cc8f3</citedby><cites>FETCH-LOGICAL-c396t-fa186431f9332578ee6eeea3a4f30b91298b150e6d1df3769c4bef8a4728cc8f3</cites><orcidid>0000-0002-1147-4928 ; 0000-0002-5696-6424 ; 0000-0003-0828-0759 ; 0000-0002-8967-5092</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2013.10.037$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24239626$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03116932$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Traoré, Ténin</creatorcontrib><creatorcontrib>Cavagnino, Andrea</creatorcontrib><creatorcontrib>Saettel, Nicolas</creatorcontrib><creatorcontrib>Radvanyi, François</creatorcontrib><creatorcontrib>Piguel, Sandrine</creatorcontrib><creatorcontrib>Bernard-Pierrot, Isabelle</creatorcontrib><creatorcontrib>Stoven, Véronique</creatorcontrib><creatorcontrib>Legraverend, Michel</creatorcontrib><title>New aminopyrimidine derivatives as inhibitors of the TAM family</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
[Display omitted]
•Novel pyrimidine-based Met inhibitors were designed and synthesized.•They inhibited potently Met and Axl, as well as Tyro3 and Mer to a lesser extend.•Molecular modeling in Met (3F82 in pdb) and in a Tyro3 model suggested a type II inhibition.</description><subject>Aminopyridines - chemical synthesis</subject><subject>Aminopyridines - chemistry</subject><subject>Aminopyridines - pharmacology</subject><subject>Docking</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Met inhibitors</subject><subject>Models, Molecular</subject><subject>Molecular modeling</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>Proto-Oncogene Proteins c-met - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-met - metabolism</subject><subject>Pyridones - chemical synthesis</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - pharmacology</subject><subject>Pyrimidine synthesis</subject><subject>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>TAM inhibitors</subject><subject>Type 2 inhibitors</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwBwhlCYsUv-IkG1BVAUUqsClry3HGiqs8ip0W9e9xFeiS1UhX586MDkLXBE8JJuJ-PYV1A7qaUkxYiKaYpSdoTFKRxYwm_BSNMaUsTijjI3Th_RpjnAiMz9GIcspyQcUYPb7Dd6Qa23abvbONLW0LUQnO7lRvd-Aj5SPbVrawfed81JmoryBazd4iE1r1_hKdGVV7uPqdE_T5_LSaL-Llx8vrfLaMdTjUx0aRTHBGTM7Cb2kGIABAMcUNw0VOaJ4VJMEgSlIalopc8wJMpnhKM60zwybobthbqVpuwqfK7WWnrFzMlvKQYUaIyBndkcDeDuzGdV9b8L1srNdQ16qFbusl4UKwlJGcB5QPqHad9w7McTfB8qBZruWgWR40H9KgOdRufi9siwbKY-nPawAeBgCCk50FJ7220GoorQPdy7Kz_1_4AQqKjmI</recordid><startdate>20131201</startdate><enddate>20131201</enddate><creator>Traoré, Ténin</creator><creator>Cavagnino, Andrea</creator><creator>Saettel, Nicolas</creator><creator>Radvanyi, François</creator><creator>Piguel, Sandrine</creator><creator>Bernard-Pierrot, Isabelle</creator><creator>Stoven, Véronique</creator><creator>Legraverend, Michel</creator><general>Elsevier Masson SAS</general><general>Elsevier</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>1XC</scope><orcidid>https://orcid.org/0000-0002-1147-4928</orcidid><orcidid>https://orcid.org/0000-0002-5696-6424</orcidid><orcidid>https://orcid.org/0000-0003-0828-0759</orcidid><orcidid>https://orcid.org/0000-0002-8967-5092</orcidid></search><sort><creationdate>20131201</creationdate><title>New aminopyrimidine derivatives as inhibitors of the TAM family</title><author>Traoré, Ténin ; Cavagnino, Andrea ; Saettel, Nicolas ; Radvanyi, François ; Piguel, Sandrine ; Bernard-Pierrot, Isabelle ; Stoven, Véronique ; Legraverend, Michel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-fa186431f9332578ee6eeea3a4f30b91298b150e6d1df3769c4bef8a4728cc8f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aminopyridines - chemical synthesis</topic><topic>Aminopyridines - chemistry</topic><topic>Aminopyridines - pharmacology</topic><topic>Docking</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Met inhibitors</topic><topic>Models, Molecular</topic><topic>Molecular modeling</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>Proto-Oncogene Proteins c-met - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-met - metabolism</topic><topic>Pyridones - chemical synthesis</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - pharmacology</topic><topic>Pyrimidine synthesis</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>TAM inhibitors</topic><topic>Type 2 inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Traoré, Ténin</creatorcontrib><creatorcontrib>Cavagnino, Andrea</creatorcontrib><creatorcontrib>Saettel, Nicolas</creatorcontrib><creatorcontrib>Radvanyi, François</creatorcontrib><creatorcontrib>Piguel, Sandrine</creatorcontrib><creatorcontrib>Bernard-Pierrot, Isabelle</creatorcontrib><creatorcontrib>Stoven, Véronique</creatorcontrib><creatorcontrib>Legraverend, Michel</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>Hyper Article en Ligne (HAL)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Traoré, Ténin</au><au>Cavagnino, Andrea</au><au>Saettel, Nicolas</au><au>Radvanyi, François</au><au>Piguel, Sandrine</au><au>Bernard-Pierrot, Isabelle</au><au>Stoven, Véronique</au><au>Legraverend, Michel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New aminopyrimidine derivatives as inhibitors of the TAM family</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2013-12-01</date><risdate>2013</risdate><volume>70</volume><spage>789</spage><epage>801</epage><pages>789-801</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
[Display omitted]
•Novel pyrimidine-based Met inhibitors were designed and synthesized.•They inhibited potently Met and Axl, as well as Tyro3 and Mer to a lesser extend.•Molecular modeling in Met (3F82 in pdb) and in a Tyro3 model suggested a type II inhibition.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>24239626</pmid><doi>10.1016/j.ejmech.2013.10.037</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-1147-4928</orcidid><orcidid>https://orcid.org/0000-0002-5696-6424</orcidid><orcidid>https://orcid.org/0000-0003-0828-0759</orcidid><orcidid>https://orcid.org/0000-0002-8967-5092</orcidid></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2013-12, Vol.70, p.789-801 |
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| subjects | Aminopyridines - chemical synthesis Aminopyridines - chemistry Aminopyridines - pharmacology Docking Dose-Response Relationship, Drug Humans Life Sciences Met inhibitors Models, Molecular Molecular modeling Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - metabolism Pyridones - chemical synthesis Pyridones - chemistry Pyridones - pharmacology Pyrimidine synthesis Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - metabolism Structure-Activity Relationship TAM inhibitors Type 2 inhibitors |
| title | New aminopyrimidine derivatives as inhibitors of the TAM family |
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