4,5-Dianilinophthalimide: A Protein-Tyrosine Kinase Inhibitor with Selectivity for the Epidermal Growth Factor Receptor Signal Transduction Pathway and Potent in vivo Antitumor Activity
Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro w...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1994-03, Vol.91 (6), p.2334-2338 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Buchdunger, Elisabeth Trinks, Uwe Mett, Helmut Regenass, Urs Muller, Marcel Meyer, Thomas McGlynn, Elaine Pinna, Lorenzo A. Traxler, Peter Lydon, Nicholas B. |
| description | Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalimide selectively inhibited both ligand-induced EGF-R and p185c-erbB2autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands. |
| doi_str_mv | 10.1073/pnas.91.6.2334 |
| format | Article |
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We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalimide selectively inhibited both ligand-induced EGF-R and p185c-erbB2autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.91.6.2334</identifier><identifier>PMID: 8134396</identifier><identifier>CODEN: PNASA6</identifier><language>eng</language><publisher>Washington, DC: National Academy of Sciences of the United States of America</publisher><subject>3T3 Cells ; Animals ; Antibodies ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Carcinoma ; Cell Division ; Cell lines ; Cellular biology ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - metabolism ; General aspects ; Hormones ; Humans ; Inhibitory concentration 50 ; Medical sciences ; Messenger RNA ; Mice ; Mice, Inbred BALB C ; Molecular Conformation ; Molecular Structure ; Pharmacology. Drug treatments ; Phosphorylation ; Phthalimides - pharmacology ; Receptors ; Signal transduction ; Signal Transduction - drug effects ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1994-03, Vol.91 (6), p.2334-2338</ispartof><rights>Copyright 1994 The National Academy of Sciences of the United States of America</rights><rights>1994 INIST-CNRS</rights><rights>Copyright National Academy of Sciences Mar 15, 1994</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c544t-3a32192e580684b42a39a4df6025366c65a6b806ff2bd1f70526ae99d2bec4253</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/91/6.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2364228$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2364228$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4119918$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8134396$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Buchdunger, Elisabeth</creatorcontrib><creatorcontrib>Trinks, Uwe</creatorcontrib><creatorcontrib>Mett, Helmut</creatorcontrib><creatorcontrib>Regenass, Urs</creatorcontrib><creatorcontrib>Muller, Marcel</creatorcontrib><creatorcontrib>Meyer, Thomas</creatorcontrib><creatorcontrib>McGlynn, Elaine</creatorcontrib><creatorcontrib>Pinna, Lorenzo A.</creatorcontrib><creatorcontrib>Traxler, Peter</creatorcontrib><creatorcontrib>Lydon, Nicholas B.</creatorcontrib><title>4,5-Dianilinophthalimide: A Protein-Tyrosine Kinase Inhibitor with Selectivity for the Epidermal Growth Factor Receptor Signal Transduction Pathway and Potent in vivo Antitumor Activity</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalimide selectively inhibited both ligand-induced EGF-R and p185c-erbB2autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.</description><subject>3T3 Cells</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Carcinoma</subject><subject>Cell Division</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - metabolism</subject><subject>General aspects</subject><subject>Hormones</subject><subject>Humans</subject><subject>Inhibitory concentration 50</subject><subject>Medical sciences</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Phthalimides - pharmacology</subject><subject>Receptors</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kk-P0zAQxSMEWsrClRNIFkJ7IsX_4saIS7XsLitWomLL2XISZ-MqtUPstPSj8e2YqKUqHDg58vu9mYnnJclLgqcEz9j7zukwlWQqppQx_iiZECxJKrjEj5MJxnSW5pzyp8mzEFYYY5nl-Cw5ywnjTIpJ8ou_y9JPVjvbWue7Jja6tWtbmQ9ojha9j8a6dLnrfbDOoC8Wuhl06xpb2Oh7tLWxQfemNWW0Gxt3qIbL2Bh01UGNfq1bdNP7LUDXuhwN30xpuvHj3j44UJe9dqEawO4dWujYbPUOaVehBbR2EVmHNnbj0dxFG4c1GOeHVs-TJ7Vug3lxOM-T79dXy8vP6d3Xm9vL-V1aZpzHlGlGiaQG_lvkvOBUM6l5VQtMMyZEKTItCtDqmhYVqWc4o0IbKStamJIDc5583NfthmJtqhKm6nWrut6udb9TXlv1t-Jsox78RnHGxGi_ONh7_2MwIaq1DaVpW-2MH4IiMBWF1QH45h9w5Yce3igoigmjM8lzgKZ7qISNhN7UxzkIVmMe1JgHJYkSaswDGF6fTn_EDwEA_e1B16HUbQ3rKG04YpwQKUl-UmYs_0c9bXPxP13VQ9tG8zMC-GoPrgKk4EhSJuAVcvYb-R3jFQ</recordid><startdate>19940315</startdate><enddate>19940315</enddate><creator>Buchdunger, Elisabeth</creator><creator>Trinks, Uwe</creator><creator>Mett, Helmut</creator><creator>Regenass, Urs</creator><creator>Muller, Marcel</creator><creator>Meyer, Thomas</creator><creator>McGlynn, Elaine</creator><creator>Pinna, Lorenzo A.</creator><creator>Traxler, Peter</creator><creator>Lydon, Nicholas B.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><scope>IQODW</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>19940315</creationdate><title>4,5-Dianilinophthalimide: A Protein-Tyrosine Kinase Inhibitor with Selectivity for the Epidermal Growth Factor Receptor Signal Transduction Pathway and Potent in vivo Antitumor Activity</title><author>Buchdunger, Elisabeth ; Trinks, Uwe ; Mett, Helmut ; Regenass, Urs ; Muller, Marcel ; Meyer, Thomas ; McGlynn, Elaine ; Pinna, Lorenzo A. ; Traxler, Peter ; Lydon, Nicholas B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c544t-3a32192e580684b42a39a4df6025366c65a6b806ff2bd1f70526ae99d2bec4253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>3T3 Cells</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Carcinoma</topic><topic>Cell Division</topic><topic>Cell lines</topic><topic>Cellular biology</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - metabolism</topic><topic>General aspects</topic><topic>Hormones</topic><topic>Humans</topic><topic>Inhibitory concentration 50</topic><topic>Medical sciences</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Pharmacology. 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We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalimide selectively inhibited both ligand-induced EGF-R and p185c-erbB2autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.</abstract><cop>Washington, DC</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>8134396</pmid><doi>10.1073/pnas.91.6.2334</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1994-03, Vol.91 (6), p.2334-2338 |
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| subjects | 3T3 Cells Animals Antibodies Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences Carcinoma Cell Division Cell lines Cellular biology ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism General aspects Hormones Humans Inhibitory concentration 50 Medical sciences Messenger RNA Mice Mice, Inbred BALB C Molecular Conformation Molecular Structure Pharmacology. Drug treatments Phosphorylation Phthalimides - pharmacology Receptors Signal transduction Signal Transduction - drug effects Tumor Cells, Cultured Tumors |
| title | 4,5-Dianilinophthalimide: A Protein-Tyrosine Kinase Inhibitor with Selectivity for the Epidermal Growth Factor Receptor Signal Transduction Pathway and Potent in vivo Antitumor Activity |
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