Small-Molecule Antagonists of Myc/Max Dimerization Inhibit Myc-Induced Transformation of Chicken Embryo Fibroblasts
Myc is a transcriptional regulator of the basic helix-loop-helix leucine zipper protein family. It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For i...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2002-03, Vol.99 (6), p.3830-3835 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Berg, Thorsten Cohen, Steven B. Desharnais, Joel Sonderegger, Corinna Maslyar, Daniel J. Goldberg, Joel Boger, Dale L. Vogt, Peter K. |
| description | Myc is a transcriptional regulator of the basic helix-loop-helix leucine zipper protein family. It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For its oncogenic activity, Myc must dimerize with the ubiquitously expressed basic helix-loop-helix leucine zipper protein Max. This requirement for dimerization may allow control of Myc activity with small molecules that interfere with Myc/Max dimerization. We have measured Myc/Max dimerization with fluorescence resonance energy transfer and have screened combinatorial chemical libraries for inhibitors of dimerization. Candidate inhibitors were isolated from a peptido-mimetics library. Inhibition of Myc/Max interaction was validated by ELISA and electrophoretic mobility-shift assay. Two of the candidate inhibitors also interfere with Myc-induced oncogenic transformation in chicken embryo fibroblast cultures. Our work provides proof of principle for the identification of small molecule inhibitors of protein-protein interactions by using high-throughput screens of combinatorial chemical libraries. |
| doi_str_mv | 10.1073/pnas.062036999 |
| format | Article |
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It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For its oncogenic activity, Myc must dimerize with the ubiquitously expressed basic helix-loop-helix leucine zipper protein Max. This requirement for dimerization may allow control of Myc activity with small molecules that interfere with Myc/Max dimerization. We have measured Myc/Max dimerization with fluorescence resonance energy transfer and have screened combinatorial chemical libraries for inhibitors of dimerization. Candidate inhibitors were isolated from a peptido-mimetics library. Inhibition of Myc/Max interaction was validated by ELISA and electrophoretic mobility-shift assay. Two of the candidate inhibitors also interfere with Myc-induced oncogenic transformation in chicken embryo fibroblast cultures. Our work provides proof of principle for the identification of small molecule inhibitors of protein-protein interactions by using high-throughput screens of combinatorial chemical libraries.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.062036999</identifier><identifier>PMID: 11891322</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Base Sequence ; Basic-Leucine Zipper Transcription Factors ; Binding sites ; Biological Sciences ; Cancer ; Cell Transformation, Neoplastic - drug effects ; Chick Embryo ; Dimerization ; Dimers ; DNA ; DNA - genetics ; DNA - metabolism ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; Electrophoretic Mobility Shift Assay ; Embryos ; Energy Transfer ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Fluorescence ; Inhibitory Concentration 50 ; Libraries ; Max protein ; Medical research ; Molecules ; Myc protein ; Pharmaceutical Preparations - chemistry ; Poultry ; Protein Binding - drug effects ; Proteins ; Proto-Oncogene Proteins c-myc - antagonists & inhibitors ; Proto-Oncogene Proteins c-myc - metabolism ; Transcription Factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2002-03, Vol.99 (6), p.3830-3835</ispartof><rights>Copyright 1993-2002 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 19, 2002</rights><rights>Copyright © 2002, The National Academy of Sciences 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c583t-3a55e589e6ff72318e31c1609b8eaee53648c83820948012cb809664875f77473</citedby><cites>FETCH-LOGICAL-c583t-3a55e589e6ff72318e31c1609b8eaee53648c83820948012cb809664875f77473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/99/6.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3058212$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3058212$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11891322$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Berg, Thorsten</creatorcontrib><creatorcontrib>Cohen, Steven B.</creatorcontrib><creatorcontrib>Desharnais, Joel</creatorcontrib><creatorcontrib>Sonderegger, Corinna</creatorcontrib><creatorcontrib>Maslyar, Daniel J.</creatorcontrib><creatorcontrib>Goldberg, Joel</creatorcontrib><creatorcontrib>Boger, Dale L.</creatorcontrib><creatorcontrib>Vogt, Peter K.</creatorcontrib><title>Small-Molecule Antagonists of Myc/Max Dimerization Inhibit Myc-Induced Transformation of Chicken Embryo Fibroblasts</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Myc is a transcriptional regulator of the basic helix-loop-helix leucine zipper protein family. It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For its oncogenic activity, Myc must dimerize with the ubiquitously expressed basic helix-loop-helix leucine zipper protein Max. This requirement for dimerization may allow control of Myc activity with small molecules that interfere with Myc/Max dimerization. We have measured Myc/Max dimerization with fluorescence resonance energy transfer and have screened combinatorial chemical libraries for inhibitors of dimerization. Candidate inhibitors were isolated from a peptido-mimetics library. Inhibition of Myc/Max interaction was validated by ELISA and electrophoretic mobility-shift assay. Two of the candidate inhibitors also interfere with Myc-induced oncogenic transformation in chicken embryo fibroblast cultures. Our work provides proof of principle for the identification of small molecule inhibitors of protein-protein interactions by using high-throughput screens of combinatorial chemical libraries.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>Basic-Leucine Zipper Transcription Factors</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Cancer</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Chick Embryo</subject><subject>Dimerization</subject><subject>Dimers</subject><subject>DNA</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electrophoretic Mobility Shift Assay</subject><subject>Embryos</subject><subject>Energy Transfer</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>Fluorescence</subject><subject>Inhibitory Concentration 50</subject><subject>Libraries</subject><subject>Max protein</subject><subject>Medical research</subject><subject>Molecules</subject><subject>Myc protein</subject><subject>Pharmaceutical Preparations - chemistry</subject><subject>Poultry</subject><subject>Protein Binding - drug effects</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-myc - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Transcription Factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcFv0zAUxi0EYmVw5QQo4sAt3bOdOPaBw1Q2qLSKA-NsOa6zujh2sR208teTqKUMxOlJ_n7fe5_1IfQSwxxDQy92XqU5MAKUCSEeoRkGgUtWCXiMZgCkKXlFqjP0LKUtAIiaw1N0hjEXmBIyQ-lLr5wrV8EZPThTXPqs7oK3KacidMVqry9W6r74YHsT7U-VbfDF0m9sa_Mklku_HrRZF7dR-dSF2B-Q0brYWP3N-OKqb-M-FNe2jaF1alz8HD3plEvmxXGeo6_XV7eLT-XN54_LxeVNqWtOc0lVXZuaC8O6riEUc0OxxgxEy40ypqas4ppTTkBUHDDRLQfBxsem7pqmaug5en_Yuxva3qy18TkqJ3fR9iruZVBW_q14u5F34YfEhIxnRv-7oz-G74NJWfY2aeOc8iYMSWJOBGV0At_-A27DEP34N0kAU2ANwyM0P0A6hpSi6U5BMMipSzl1KU9djoY3D-P_wY_ljcDrIzAZf8tCSCYpp_Ag_3912Q3OZXOfR_DVAdymHOKJpFBzggn9BSCrvAk</recordid><startdate>20020319</startdate><enddate>20020319</enddate><creator>Berg, Thorsten</creator><creator>Cohen, Steven B.</creator><creator>Desharnais, Joel</creator><creator>Sonderegger, Corinna</creator><creator>Maslyar, Daniel J.</creator><creator>Goldberg, Joel</creator><creator>Boger, Dale L.</creator><creator>Vogt, Peter K.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</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>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>20020319</creationdate><title>Small-Molecule Antagonists of Myc/Max Dimerization Inhibit Myc-Induced Transformation of Chicken Embryo Fibroblasts</title><author>Berg, Thorsten ; Cohen, Steven B. ; Desharnais, Joel ; Sonderegger, Corinna ; Maslyar, Daniel J. ; Goldberg, Joel ; Boger, Dale L. ; Vogt, Peter K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c583t-3a55e589e6ff72318e31c1609b8eaee53648c83820948012cb809664875f77473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Base Sequence</topic><topic>Basic-Leucine Zipper Transcription Factors</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Cancer</topic><topic>Cell Transformation, Neoplastic - drug effects</topic><topic>Chick Embryo</topic><topic>Dimerization</topic><topic>Dimers</topic><topic>DNA</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electrophoretic Mobility Shift Assay</topic><topic>Embryos</topic><topic>Energy Transfer</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - pathology</topic><topic>Fluorescence</topic><topic>Inhibitory Concentration 50</topic><topic>Libraries</topic><topic>Max protein</topic><topic>Medical research</topic><topic>Molecules</topic><topic>Myc protein</topic><topic>Pharmaceutical Preparations - chemistry</topic><topic>Poultry</topic><topic>Protein Binding - drug effects</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-myc - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Transcription Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Berg, Thorsten</creatorcontrib><creatorcontrib>Cohen, Steven B.</creatorcontrib><creatorcontrib>Desharnais, Joel</creatorcontrib><creatorcontrib>Sonderegger, Corinna</creatorcontrib><creatorcontrib>Maslyar, Daniel J.</creatorcontrib><creatorcontrib>Goldberg, Joel</creatorcontrib><creatorcontrib>Boger, Dale L.</creatorcontrib><creatorcontrib>Vogt, Peter K.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Berg, Thorsten</au><au>Cohen, Steven B.</au><au>Desharnais, Joel</au><au>Sonderegger, Corinna</au><au>Maslyar, Daniel J.</au><au>Goldberg, Joel</au><au>Boger, Dale L.</au><au>Vogt, Peter K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small-Molecule Antagonists of Myc/Max Dimerization Inhibit Myc-Induced Transformation of Chicken Embryo Fibroblasts</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2002-03-19</date><risdate>2002</risdate><volume>99</volume><issue>6</issue><spage>3830</spage><epage>3835</epage><pages>3830-3835</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Myc is a transcriptional regulator of the basic helix-loop-helix leucine zipper protein family. It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For its oncogenic activity, Myc must dimerize with the ubiquitously expressed basic helix-loop-helix leucine zipper protein Max. This requirement for dimerization may allow control of Myc activity with small molecules that interfere with Myc/Max dimerization. We have measured Myc/Max dimerization with fluorescence resonance energy transfer and have screened combinatorial chemical libraries for inhibitors of dimerization. Candidate inhibitors were isolated from a peptido-mimetics library. Inhibition of Myc/Max interaction was validated by ELISA and electrophoretic mobility-shift assay. Two of the candidate inhibitors also interfere with Myc-induced oncogenic transformation in chicken embryo fibroblast cultures. Our work provides proof of principle for the identification of small molecule inhibitors of protein-protein interactions by using high-throughput screens of combinatorial chemical libraries.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>11891322</pmid><doi>10.1073/pnas.062036999</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Base Sequence Basic-Leucine Zipper Transcription Factors Binding sites Biological Sciences Cancer Cell Transformation, Neoplastic - drug effects Chick Embryo Dimerization Dimers DNA DNA - genetics DNA - metabolism DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Electrophoretic Mobility Shift Assay Embryos Energy Transfer Enzyme-Linked Immunosorbent Assay Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology Fluorescence Inhibitory Concentration 50 Libraries Max protein Medical research Molecules Myc protein Pharmaceutical Preparations - chemistry Poultry Protein Binding - drug effects Proteins Proto-Oncogene Proteins c-myc - antagonists & inhibitors Proto-Oncogene Proteins c-myc - metabolism Transcription Factors |
| title | Small-Molecule Antagonists of Myc/Max Dimerization Inhibit Myc-Induced Transformation of Chicken Embryo Fibroblasts |
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