The central valine concept provides an entry in a new class of non peptide inhibitors of the p53–MDM2 interaction
Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein–protein interaction, we have devised a ligand design concept exploiting the central position of...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (10), p.3498-3502 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Furet, Pascal Chène, Patrick De Pover, Alain Valat, Thérèse Stachyra Lisztwan, Joanna Hergovich Kallen, Joerg Masuya, Keiichi |
| description | Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein–protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53–MDM2 interaction. |
| doi_str_mv | 10.1016/j.bmcl.2012.03.083 |
| format | Article |
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Drug treatments ; Protein Binding ; protein-protein interactions ; Protein–protein interaction inhibitors ; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Structure-based design ; Tumor Suppressor Protein p53 - antagonists & inhibitors ; Tumor Suppressor Protein p53 - metabolism ; valine ; Valine - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-05, Vol.22 (10), p.3498-3502</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. 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In our search for non peptide inhibitors of this protein–protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53–MDM2 interaction.</description><subject>Anticancer agents</subject><subject>antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>p53–MDM2 inhibitors</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>protein-protein interactions</subject><subject>Protein–protein interaction inhibitors</subject><subject>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Structure-based design</subject><subject>Tumor Suppressor Protein p53 - antagonists & inhibitors</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>valine</subject><subject>Valine - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c1u1DAQB3ALgehSeAEO4AtSLwnjj3gdiQsq5UNqxYFW4mY5zoR6lbWDnV3UG-_AG_IkOOwCN06WNT-P7f8Q8pRBzYCpl5u627qx5sB4DaIGLe6RFZNKVkJCc5-soFVQ6VZ-PiGPct4AMAlSPiQnnDewbhVfkXx9i9RhmJMd6d6OPpRtDA6nmU4p7n2PmdpAF3FHfaCWBvxG3WhzpnGgIQY6FVxcqd76zs8x_a7MpfHUiJ_ff1y9ueKlOGOybvYxPCYPBjtmfHJcT8nN24vr8_fV5cd3H85fX1ZOMpgrgcy167bjSg2KOw6i77hVEng3OOi0QA1tM7i-UwPvu7ZhDNeopWs19JJrcUrODn3LR77uMM9m67PDcbQB4y6bEiJrJAclCuUH6lLMOeFgpuS3Nt0VtDhlNmYJ2yxhGxCmhF0OPTv233Vb7P8e-ZNuAS-OwGZnxyHZ4Hz-5xqttQIo7vnBDTYa-yUVc_Op3NSUiQlQzXLVq4PAktfeYzLZeSxj6n1CN5s--v-99BcJeacJ</recordid><startdate>20120515</startdate><enddate>20120515</enddate><creator>Furet, Pascal</creator><creator>Chène, Patrick</creator><creator>De Pover, Alain</creator><creator>Valat, Thérèse Stachyra</creator><creator>Lisztwan, Joanna Hergovich</creator><creator>Kallen, Joerg</creator><creator>Masuya, Keiichi</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><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>7X8</scope></search><sort><creationdate>20120515</creationdate><title>The central valine concept provides an entry in a new class of non peptide inhibitors of the p53–MDM2 interaction</title><author>Furet, Pascal ; Chène, Patrick ; De Pover, Alain ; Valat, Thérèse Stachyra ; Lisztwan, Joanna Hergovich ; Kallen, Joerg ; Masuya, Keiichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-3e1c979b266f62c203db2a6402bfc0b83e8095fcdb6f2db9511e7e84c980d4283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Anticancer agents</topic><topic>antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>p53–MDM2 inhibitors</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>protein-protein interactions</topic><topic>Protein–protein interaction inhibitors</topic><topic>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Structure-based design</topic><topic>Tumor Suppressor Protein p53 - antagonists & inhibitors</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>valine</topic><topic>Valine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Furet, Pascal</creatorcontrib><creatorcontrib>Chène, Patrick</creatorcontrib><creatorcontrib>De Pover, Alain</creatorcontrib><creatorcontrib>Valat, Thérèse Stachyra</creatorcontrib><creatorcontrib>Lisztwan, Joanna Hergovich</creatorcontrib><creatorcontrib>Kallen, Joerg</creatorcontrib><creatorcontrib>Masuya, Keiichi</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Furet, Pascal</au><au>Chène, Patrick</au><au>De Pover, Alain</au><au>Valat, Thérèse Stachyra</au><au>Lisztwan, Joanna Hergovich</au><au>Kallen, Joerg</au><au>Masuya, Keiichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The central valine concept provides an entry in a new class of non peptide inhibitors of the p53–MDM2 interaction</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-05-15</date><risdate>2012</risdate><volume>22</volume><issue>10</issue><spage>3498</spage><epage>3502</epage><pages>3498-3502</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. 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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-05, Vol.22 (10), p.3498-3502 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Anticancer agents antineoplastic agents Biological and medical sciences Medical sciences Models, Molecular p53–MDM2 inhibitors Pharmacology. Drug treatments Protein Binding protein-protein interactions Protein–protein interaction inhibitors Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors Proto-Oncogene Proteins c-mdm2 - metabolism Structure-based design Tumor Suppressor Protein p53 - antagonists & inhibitors Tumor Suppressor Protein p53 - metabolism valine Valine - metabolism |
| title | The central valine concept provides an entry in a new class of non peptide inhibitors of the p53–MDM2 interaction |
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