Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor
Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicit...
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| Veröffentlicht in: | European journal of medicinal chemistry 2014-03, Vol.75, p.354-374 |
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| container_title | European journal of medicinal chemistry |
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| creator | Bugge, Steffen Kaspersen, Svein Jacob Larsen, Synne Nonstad, Unni Bjørkøy, Geir Sundby, Eirik Hoff, Bård Helge |
| description | Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 |
| doi_str_mv | 10.1016/j.ejmech.2014.01.042 |
| format | Article |
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•SAR study on EGFR was performed with benzylamine based thienopyrimidines (46 ex.).•Three highly active derivatives discovered (IC50 < 1 nM).•The most active drug candidate was equipotent to Erlotinib in enzymatic assays.•Cellular potency compared with Erlotinib in Ba/F3 cells and human cancer cell lines.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.01.042</identifier><identifier>PMID: 24556149</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Benzylamine ; Benzylamines - chemistry ; Cell Line, Tumor ; EGFR-TK ; Erlotinib ; Humans ; Models, Molecular ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - metabolism ; SAR ; Suzuki-coupling ; Thienopyrimidine</subject><ispartof>European journal of medicinal chemistry, 2014-03, Vol.75, p.354-374</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-5e860dc6dfe19eb59a5f4ec2915963196f97f09513fff134c0f034ffae23e593</citedby><cites>FETCH-LOGICAL-c428t-5e860dc6dfe19eb59a5f4ec2915963196f97f09513fff134c0f034ffae23e593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523414000889$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24556149$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bugge, Steffen</creatorcontrib><creatorcontrib>Kaspersen, Svein Jacob</creatorcontrib><creatorcontrib>Larsen, Synne</creatorcontrib><creatorcontrib>Nonstad, Unni</creatorcontrib><creatorcontrib>Bjørkøy, Geir</creatorcontrib><creatorcontrib>Sundby, Eirik</creatorcontrib><creatorcontrib>Hoff, Bård Helge</creatorcontrib><title>Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.
[Display omitted]
•SAR study on EGFR was performed with benzylamine based thienopyrimidines (46 ex.).•Three highly active derivatives discovered (IC50 < 1 nM).•The most active drug candidate was equipotent to Erlotinib in enzymatic assays.•Cellular potency compared with Erlotinib in Ba/F3 cells and human cancer cell lines.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzylamine</subject><subject>Benzylamines - chemistry</subject><subject>Cell Line, Tumor</subject><subject>EGFR-TK</subject><subject>Erlotinib</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>SAR</subject><subject>Suzuki-coupling</subject><subject>Thienopyrimidine</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u1DAUhS0EotPCGyDkJZuE6790vEFCVX-QKiFB95bHvm48SuLBdipl13fgDXkSUqawZHU337lH5yPkHYOWAes-7lvcj-j6lgOTLbAWJH9BNuy82zaCK_mSbIBz0Sgu5Ak5LWUPAKoDeE1OuFSqY1JvyPi95tnVOeOvx5_W1fgQ60JLnf1CB7Q-Tve0Jho9TjWG6GyNaaIpUEv7eN8PC_0TQlr7iFM6LDmOcU0h3dmCnl5eX32jcerjLtaU35BXwQ4F3z7fM3J3dXl3cdPcfr3-cvH5tnGSb2ujcNuBd50PyDTulLYqSHRcM6U7wXQX9HkArZgIITAhHQQQMgSLXKDS4ox8OL495PRjxlLNGIvDYbATprkYpkBxpbiUKyqPqMuplIzBHNYFNi-GgXnybPbm6Nk8eTbAzOp5jb1_bph3I_p_ob9iV-DTEcB15kPEbIpbBTn0MaOrxqf4_4bfmy6TNQ</recordid><startdate>20140321</startdate><enddate>20140321</enddate><creator>Bugge, Steffen</creator><creator>Kaspersen, Svein Jacob</creator><creator>Larsen, Synne</creator><creator>Nonstad, Unni</creator><creator>Bjørkøy, Geir</creator><creator>Sundby, Eirik</creator><creator>Hoff, Bård Helge</creator><general>Elsevier Masson SAS</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></search><sort><creationdate>20140321</creationdate><title>Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor</title><author>Bugge, Steffen ; Kaspersen, Svein Jacob ; Larsen, Synne ; Nonstad, Unni ; Bjørkøy, Geir ; Sundby, Eirik ; Hoff, Bård Helge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-5e860dc6dfe19eb59a5f4ec2915963196f97f09513fff134c0f034ffae23e593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzylamine</topic><topic>Benzylamines - chemistry</topic><topic>Cell Line, Tumor</topic><topic>EGFR-TK</topic><topic>Erlotinib</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>SAR</topic><topic>Suzuki-coupling</topic><topic>Thienopyrimidine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bugge, Steffen</creatorcontrib><creatorcontrib>Kaspersen, Svein Jacob</creatorcontrib><creatorcontrib>Larsen, Synne</creatorcontrib><creatorcontrib>Nonstad, Unni</creatorcontrib><creatorcontrib>Bjørkøy, Geir</creatorcontrib><creatorcontrib>Sundby, Eirik</creatorcontrib><creatorcontrib>Hoff, Bård Helge</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bugge, Steffen</au><au>Kaspersen, Svein Jacob</au><au>Larsen, Synne</au><au>Nonstad, Unni</au><au>Bjørkøy, Geir</au><au>Sundby, Eirik</au><au>Hoff, Bård Helge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2014-03-21</date><risdate>2014</risdate><volume>75</volume><spage>354</spage><epage>374</epage><pages>354-374</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.
[Display omitted]
•SAR study on EGFR was performed with benzylamine based thienopyrimidines (46 ex.).•Three highly active derivatives discovered (IC50 < 1 nM).•The most active drug candidate was equipotent to Erlotinib in enzymatic assays.•Cellular potency compared with Erlotinib in Ba/F3 cells and human cancer cell lines.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>24556149</pmid><doi>10.1016/j.ejmech.2014.01.042</doi><tpages>21</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Benzylamine Benzylamines - chemistry Cell Line, Tumor EGFR-TK Erlotinib Humans Models, Molecular Neoplasms - drug therapy Neoplasms - metabolism Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - metabolism SAR Suzuki-coupling Thienopyrimidine |
| title | Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor |
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