Identification of a novel family of BRAF(V600E) inhibitors
The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbo...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2012-06, Vol.55 (11), p.5220-5230 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 5230 |
|---|---|
| container_issue | 11 |
| container_start_page | 5220 |
| container_title | Journal of medicinal chemistry |
| container_volume | 55 |
| creator | Qin, Jie Xie, Peng Ventocilla, Christian Zhou, Guoqiang Vultur, Adina Chen, Quan Liu, Qin Herlyn, Meenhard Winkler, Jeffrey Marmorstein, Ronen |
| description | The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed. |
| doi_str_mv | 10.1021/jm3004416 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_1045032</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1020827659</sourcerecordid><originalsourceid>FETCH-LOGICAL-o238t-fcbc77b456d98afb437fe42856c17348364ccee9dcd268e42cea531d291b89223</originalsourceid><addsrcrecordid>eNo10M1Kw0AUBeBBFFurC19Agqu6iN6585OJu1paLRQEUbdhMpnQKUmmZqZC396W1tWFcz7O4hJyS-GRAtKndcsAOKfyjAypQEi5An5OhgCIKUpkA3IVwhoAGEV2SQaIgmUU8iF5XlS2i652Rkfnu8TXiU46_2ubpNata3aH5OVjMh9_S4DZQ-K6lStd9H24Jhe1boK9Od0R-ZrPPqdv6fL9dTGdLFOPTMW0NqXJspILWeVK1yVnWW05KiENzRhXTHJjrM0rU6FU-8ZYLRitMKelyhHZiNwfd32IrgjGRWtWxnedNbGgwAWwAxof0ab3P1sbYtG6YGzT6M76bdg7BIWZFPme3p3otmxtVWx61-p-V_w_hf0BCARfUg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1020827659</pqid></control><display><type>article</type><title>Identification of a novel family of BRAF(V600E) inhibitors</title><source>MEDLINE</source><source>ACS Publications</source><creator>Qin, Jie ; Xie, Peng ; Ventocilla, Christian ; Zhou, Guoqiang ; Vultur, Adina ; Chen, Quan ; Liu, Qin ; Herlyn, Meenhard ; Winkler, Jeffrey ; Marmorstein, Ronen</creator><creatorcontrib>Qin, Jie ; Xie, Peng ; Ventocilla, Christian ; Zhou, Guoqiang ; Vultur, Adina ; Chen, Quan ; Liu, Qin ; Herlyn, Meenhard ; Winkler, Jeffrey ; Marmorstein, Ronen ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3004416</identifier><identifier>PMID: 22537109</identifier><language>eng</language><publisher>United States</publisher><subject>60 APPLIED LIFE SCIENCES ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; BASIC BIOLOGICAL SCIENCES ; Cell Line, Tumor ; Cell Proliferation - drug effects ; CHEMISTRY ; CRYSTAL STRUCTURE ; Crystallography, X-Ray ; Drug Screening Assays, Antitumor ; ENZYME IMMUNOASSAY ; Enzyme-Linked Immunosorbent Assay ; High-Throughput Screening Assays ; Humans ; Hydroquinones - chemical synthesis ; Hydroquinones - chemistry ; Hydroquinones - pharmacology ; IN VITRO ; LIABILITIES ; MAP Kinase Signaling System ; Melanoma ; MELANOMAS ; Models, Molecular ; Molecular Structure ; Mutation ; NAPHTHOLS ; Naphthols - chemical synthesis ; Naphthols - chemistry ; Naphthols - pharmacology ; PHOSPHOTRANSFERASES ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - chemistry ; Proto-Oncogene Proteins B-raf - genetics ; RESIDUES ; Stereoisomerism ; Structure-Activity Relationship ; VALINE</subject><ispartof>Journal of medicinal chemistry, 2012-06, Vol.55 (11), p.5220-5230</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22537109$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1045032$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Qin, Jie</creatorcontrib><creatorcontrib>Xie, Peng</creatorcontrib><creatorcontrib>Ventocilla, Christian</creatorcontrib><creatorcontrib>Zhou, Guoqiang</creatorcontrib><creatorcontrib>Vultur, Adina</creatorcontrib><creatorcontrib>Chen, Quan</creatorcontrib><creatorcontrib>Liu, Qin</creatorcontrib><creatorcontrib>Herlyn, Meenhard</creatorcontrib><creatorcontrib>Winkler, Jeffrey</creatorcontrib><creatorcontrib>Marmorstein, Ronen</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Identification of a novel family of BRAF(V600E) inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>CHEMISTRY</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallography, X-Ray</subject><subject>Drug Screening Assays, Antitumor</subject><subject>ENZYME IMMUNOASSAY</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Hydroquinones - chemical synthesis</subject><subject>Hydroquinones - chemistry</subject><subject>Hydroquinones - pharmacology</subject><subject>IN VITRO</subject><subject>LIABILITIES</subject><subject>MAP Kinase Signaling System</subject><subject>Melanoma</subject><subject>MELANOMAS</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Mutation</subject><subject>NAPHTHOLS</subject><subject>Naphthols - chemical synthesis</subject><subject>Naphthols - chemistry</subject><subject>Naphthols - pharmacology</subject><subject>PHOSPHOTRANSFERASES</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - chemistry</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>RESIDUES</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>VALINE</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo10M1Kw0AUBeBBFFurC19Agqu6iN6585OJu1paLRQEUbdhMpnQKUmmZqZC396W1tWFcz7O4hJyS-GRAtKndcsAOKfyjAypQEi5An5OhgCIKUpkA3IVwhoAGEV2SQaIgmUU8iF5XlS2i652Rkfnu8TXiU46_2ubpNata3aH5OVjMh9_S4DZQ-K6lStd9H24Jhe1boK9Od0R-ZrPPqdv6fL9dTGdLFOPTMW0NqXJspILWeVK1yVnWW05KiENzRhXTHJjrM0rU6FU-8ZYLRitMKelyhHZiNwfd32IrgjGRWtWxnedNbGgwAWwAxof0ab3P1sbYtG6YGzT6M76bdg7BIWZFPme3p3otmxtVWx61-p-V_w_hf0BCARfUg</recordid><startdate>20120614</startdate><enddate>20120614</enddate><creator>Qin, Jie</creator><creator>Xie, Peng</creator><creator>Ventocilla, Christian</creator><creator>Zhou, Guoqiang</creator><creator>Vultur, Adina</creator><creator>Chen, Quan</creator><creator>Liu, Qin</creator><creator>Herlyn, Meenhard</creator><creator>Winkler, Jeffrey</creator><creator>Marmorstein, Ronen</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20120614</creationdate><title>Identification of a novel family of BRAF(V600E) inhibitors</title><author>Qin, Jie ; Xie, Peng ; Ventocilla, Christian ; Zhou, Guoqiang ; Vultur, Adina ; Chen, Quan ; Liu, Qin ; Herlyn, Meenhard ; Winkler, Jeffrey ; Marmorstein, Ronen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-o238t-fcbc77b456d98afb437fe42856c17348364ccee9dcd268e42cea531d291b89223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>CHEMISTRY</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallography, X-Ray</topic><topic>Drug Screening Assays, Antitumor</topic><topic>ENZYME IMMUNOASSAY</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Hydroquinones - chemical synthesis</topic><topic>Hydroquinones - chemistry</topic><topic>Hydroquinones - pharmacology</topic><topic>IN VITRO</topic><topic>LIABILITIES</topic><topic>MAP Kinase Signaling System</topic><topic>Melanoma</topic><topic>MELANOMAS</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Mutation</topic><topic>NAPHTHOLS</topic><topic>Naphthols - chemical synthesis</topic><topic>Naphthols - chemistry</topic><topic>Naphthols - pharmacology</topic><topic>PHOSPHOTRANSFERASES</topic><topic>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins B-raf - chemistry</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>RESIDUES</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>VALINE</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qin, Jie</creatorcontrib><creatorcontrib>Xie, Peng</creatorcontrib><creatorcontrib>Ventocilla, Christian</creatorcontrib><creatorcontrib>Zhou, Guoqiang</creatorcontrib><creatorcontrib>Vultur, Adina</creatorcontrib><creatorcontrib>Chen, Quan</creatorcontrib><creatorcontrib>Liu, Qin</creatorcontrib><creatorcontrib>Herlyn, Meenhard</creatorcontrib><creatorcontrib>Winkler, Jeffrey</creatorcontrib><creatorcontrib>Marmorstein, Ronen</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qin, Jie</au><au>Xie, Peng</au><au>Ventocilla, Christian</au><au>Zhou, Guoqiang</au><au>Vultur, Adina</au><au>Chen, Quan</au><au>Liu, Qin</au><au>Herlyn, Meenhard</au><au>Winkler, Jeffrey</au><au>Marmorstein, Ronen</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a novel family of BRAF(V600E) inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2012-06-14</date><risdate>2012</risdate><volume>55</volume><issue>11</issue><spage>5220</spage><epage>5230</epage><pages>5220-5230</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.</abstract><cop>United States</cop><pmid>22537109</pmid><doi>10.1021/jm3004416</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2012-06, Vol.55 (11), p.5220-5230 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1045032 |
| source | MEDLINE; ACS Publications |
| subjects | 60 APPLIED LIFE SCIENCES Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology BASIC BIOLOGICAL SCIENCES Cell Line, Tumor Cell Proliferation - drug effects CHEMISTRY CRYSTAL STRUCTURE Crystallography, X-Ray Drug Screening Assays, Antitumor ENZYME IMMUNOASSAY Enzyme-Linked Immunosorbent Assay High-Throughput Screening Assays Humans Hydroquinones - chemical synthesis Hydroquinones - chemistry Hydroquinones - pharmacology IN VITRO LIABILITIES MAP Kinase Signaling System Melanoma MELANOMAS Models, Molecular Molecular Structure Mutation NAPHTHOLS Naphthols - chemical synthesis Naphthols - chemistry Naphthols - pharmacology PHOSPHOTRANSFERASES Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - chemistry Proto-Oncogene Proteins B-raf - genetics RESIDUES Stereoisomerism Structure-Activity Relationship VALINE |
| title | Identification of a novel family of BRAF(V600E) inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T04%3A58%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20a%20novel%20family%20of%20BRAF(V600E)%20inhibitors&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Qin,%20Jie&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2012-06-14&rft.volume=55&rft.issue=11&rft.spage=5220&rft.epage=5230&rft.pages=5220-5230&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm3004416&rft_dat=%3Cproquest_osti_%3E1020827659%3C/proquest_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1020827659&rft_id=info:pmid/22537109&rfr_iscdi=true |