Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90
Indazole fragments were identified by a fragment based approach and optimized by SBDD using information from X-ray structures of ligands bound to the molecular chaperone Hsp90. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity. Inhibi...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4396-4403 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 4403 |
|---|---|
| container_issue | 13 |
| container_start_page | 4396 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 22 |
| creator | Buchstaller, Hans-Peter Eggenweiler, Hans-Michael Sirrenberg, Christian Grädler, Ulrich Musil, Djordje Hoppe, Edmund Zimmermann, Astrid Schwartz, Harry März, Joachim Bomke, Jörg Wegener, Ansgar Wolf, Michael |
| description | Indazole fragments were identified by a fragment based approach and optimized by SBDD using information from X-ray structures of ligands bound to the molecular chaperone Hsp90. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines. |
| doi_str_mv | 10.1016/j.bmcl.2012.04.121 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1034828092</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X1200580X</els_id><sourcerecordid>1020830745</sourcerecordid><originalsourceid>FETCH-LOGICAL-c443t-d73ef8d6ccabec36047fab6ae9989205ad7e2a091578f9a754c48d548af61a23</originalsourceid><addsrcrecordid>eNqN0T1vFDEQBmALgcgR-AMUsA0SzS7jj_2wRIMiQpAiURAkOmvWnk188q4P-y7K8evx6Q7oEJWbZ17b8zL2kkPDgXfv1s0429AI4KIB1XDBH7EVV52qpYL2MVuB7qAetPp-xp7lvAbgCpR6ys6E6KTQUq4YXSa8nWnZ1iNmcpXz2cZ7SvsqTtXd3qX4sK_94vBnDFRbTGN8wNk7yhXmaik0VHnGEKq5ALsLVPnlzo9-G1M-ZFzljYbn7MmEIdOL03nObi4_3lxc1ddfPn2--HBdW6Xktna9pGlwnbU4kpUdqH7CsUPSetACWnQ9CQTN236YNPatsmpwrRpw6jgKec7eHmM3Kf7YUd6auXyHQsCF4i4bDlINYgD9P1TAIKFXbaHiSG2KOSeazCb5GdO-IHMowqzNoQhzKMKAMqWIMvTqlL8bZ3J_Rn5vvoA3J4DZYpgSLtbnv64DLXuui3t9dBNGg7epmG9fy01taVPCIPoi3h8Flc3ee0omW0-LJecT2a1x0f_rpb8Ax3ywZA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1020830745</pqid></control><display><type>article</type><title>Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Buchstaller, Hans-Peter ; Eggenweiler, Hans-Michael ; Sirrenberg, Christian ; Grädler, Ulrich ; Musil, Djordje ; Hoppe, Edmund ; Zimmermann, Astrid ; Schwartz, Harry ; März, Joachim ; Bomke, Jörg ; Wegener, Ansgar ; Wolf, Michael</creator><creatorcontrib>Buchstaller, Hans-Peter ; Eggenweiler, Hans-Michael ; Sirrenberg, Christian ; Grädler, Ulrich ; Musil, Djordje ; Hoppe, Edmund ; Zimmermann, Astrid ; Schwartz, Harry ; März, Joachim ; Bomke, Jörg ; Wegener, Ansgar ; Wolf, Michael</creatorcontrib><description>Indazole fragments were identified by a fragment based approach and optimized by SBDD using information from X-ray structures of ligands bound to the molecular chaperone Hsp90. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.04.121</identifier><identifier>PMID: 22632933</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Amides - chemistry ; Amides - toxicity ; Anti-cancer drug ; Binding Sites ; Biological and medical sciences ; Cancer ; Cell Line, Tumor ; Cell Survival - drug effects ; Chaperones ; chemotypes ; Computer Simulation ; Crystallography, X-Ray ; Docking ; Drug Evaluation, Preclinical ; Evolution ; Fragments ; Heat shock protein 90 ; Hsp90 ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - metabolism ; Hsp90 protein ; Humans ; Indazoles ; Indazoles - chemistry ; Ionizing radiation ; Medical sciences ; molecular chaperones ; Molecular weight ; Pharmacology. Drug treatments ; Protein Structure, Tertiary ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - toxicity ; Structure-Activity Relationship ; Tumor cell lines ; X-radiation ; X-ray structure</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-07, Vol.22 (13), p.4396-4403</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-d73ef8d6ccabec36047fab6ae9989205ad7e2a091578f9a754c48d548af61a23</citedby><cites>FETCH-LOGICAL-c443t-d73ef8d6ccabec36047fab6ae9989205ad7e2a091578f9a754c48d548af61a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X1200580X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26093719$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22632933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Buchstaller, Hans-Peter</creatorcontrib><creatorcontrib>Eggenweiler, Hans-Michael</creatorcontrib><creatorcontrib>Sirrenberg, Christian</creatorcontrib><creatorcontrib>Grädler, Ulrich</creatorcontrib><creatorcontrib>Musil, Djordje</creatorcontrib><creatorcontrib>Hoppe, Edmund</creatorcontrib><creatorcontrib>Zimmermann, Astrid</creatorcontrib><creatorcontrib>Schwartz, Harry</creatorcontrib><creatorcontrib>März, Joachim</creatorcontrib><creatorcontrib>Bomke, Jörg</creatorcontrib><creatorcontrib>Wegener, Ansgar</creatorcontrib><creatorcontrib>Wolf, Michael</creatorcontrib><title>Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Indazole fragments were identified by a fragment based approach and optimized by SBDD using information from X-ray structures of ligands bound to the molecular chaperone Hsp90. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.</description><subject>Amides - chemistry</subject><subject>Amides - toxicity</subject><subject>Anti-cancer drug</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chaperones</subject><subject>chemotypes</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Docking</subject><subject>Drug Evaluation, Preclinical</subject><subject>Evolution</subject><subject>Fragments</subject><subject>Heat shock protein 90</subject><subject>Hsp90</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Hsp90 protein</subject><subject>Humans</subject><subject>Indazoles</subject><subject>Indazoles - chemistry</subject><subject>Ionizing radiation</subject><subject>Medical sciences</subject><subject>molecular chaperones</subject><subject>Molecular weight</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Structure, Tertiary</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - toxicity</subject><subject>Structure-Activity Relationship</subject><subject>Tumor cell lines</subject><subject>X-radiation</subject><subject>X-ray structure</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>eNqN0T1vFDEQBmALgcgR-AMUsA0SzS7jj_2wRIMiQpAiURAkOmvWnk188q4P-y7K8evx6Q7oEJWbZ17b8zL2kkPDgXfv1s0429AI4KIB1XDBH7EVV52qpYL2MVuB7qAetPp-xp7lvAbgCpR6ys6E6KTQUq4YXSa8nWnZ1iNmcpXz2cZ7SvsqTtXd3qX4sK_94vBnDFRbTGN8wNk7yhXmaik0VHnGEKq5ALsLVPnlzo9-G1M-ZFzljYbn7MmEIdOL03nObi4_3lxc1ddfPn2--HBdW6Xktna9pGlwnbU4kpUdqH7CsUPSetACWnQ9CQTN236YNPatsmpwrRpw6jgKec7eHmM3Kf7YUd6auXyHQsCF4i4bDlINYgD9P1TAIKFXbaHiSG2KOSeazCb5GdO-IHMowqzNoQhzKMKAMqWIMvTqlL8bZ3J_Rn5vvoA3J4DZYpgSLtbnv64DLXuui3t9dBNGg7epmG9fy01taVPCIPoi3h8Flc3ee0omW0-LJecT2a1x0f_rpb8Ax3ywZA</recordid><startdate>20120701</startdate><enddate>20120701</enddate><creator>Buchstaller, Hans-Peter</creator><creator>Eggenweiler, Hans-Michael</creator><creator>Sirrenberg, Christian</creator><creator>Grädler, Ulrich</creator><creator>Musil, Djordje</creator><creator>Hoppe, Edmund</creator><creator>Zimmermann, Astrid</creator><creator>Schwartz, Harry</creator><creator>März, Joachim</creator><creator>Bomke, Jörg</creator><creator>Wegener, Ansgar</creator><creator>Wolf, Michael</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120701</creationdate><title>Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90</title><author>Buchstaller, Hans-Peter ; Eggenweiler, Hans-Michael ; Sirrenberg, Christian ; Grädler, Ulrich ; Musil, Djordje ; Hoppe, Edmund ; Zimmermann, Astrid ; Schwartz, Harry ; März, Joachim ; Bomke, Jörg ; Wegener, Ansgar ; Wolf, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-d73ef8d6ccabec36047fab6ae9989205ad7e2a091578f9a754c48d548af61a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Amides - chemistry</topic><topic>Amides - toxicity</topic><topic>Anti-cancer drug</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chaperones</topic><topic>chemotypes</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray</topic><topic>Docking</topic><topic>Drug Evaluation, Preclinical</topic><topic>Evolution</topic><topic>Fragments</topic><topic>Heat shock protein 90</topic><topic>Hsp90</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Hsp90 protein</topic><topic>Humans</topic><topic>Indazoles</topic><topic>Indazoles - chemistry</topic><topic>Ionizing radiation</topic><topic>Medical sciences</topic><topic>molecular chaperones</topic><topic>Molecular weight</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Structure, Tertiary</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - toxicity</topic><topic>Structure-Activity Relationship</topic><topic>Tumor cell lines</topic><topic>X-radiation</topic><topic>X-ray structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Buchstaller, Hans-Peter</creatorcontrib><creatorcontrib>Eggenweiler, Hans-Michael</creatorcontrib><creatorcontrib>Sirrenberg, Christian</creatorcontrib><creatorcontrib>Grädler, Ulrich</creatorcontrib><creatorcontrib>Musil, Djordje</creatorcontrib><creatorcontrib>Hoppe, Edmund</creatorcontrib><creatorcontrib>Zimmermann, Astrid</creatorcontrib><creatorcontrib>Schwartz, Harry</creatorcontrib><creatorcontrib>März, Joachim</creatorcontrib><creatorcontrib>Bomke, Jörg</creatorcontrib><creatorcontrib>Wegener, Ansgar</creatorcontrib><creatorcontrib>Wolf, Michael</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buchstaller, Hans-Peter</au><au>Eggenweiler, Hans-Michael</au><au>Sirrenberg, Christian</au><au>Grädler, Ulrich</au><au>Musil, Djordje</au><au>Hoppe, Edmund</au><au>Zimmermann, Astrid</au><au>Schwartz, Harry</au><au>März, Joachim</au><au>Bomke, Jörg</au><au>Wegener, Ansgar</au><au>Wolf, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-07-01</date><risdate>2012</risdate><volume>22</volume><issue>13</issue><spage>4396</spage><epage>4403</epage><pages>4396-4403</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Indazole fragments were identified by a fragment based approach and optimized by SBDD using information from X-ray structures of ligands bound to the molecular chaperone Hsp90. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22632933</pmid><doi>10.1016/j.bmcl.2012.04.121</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-07, Vol.22 (13), p.4396-4403 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1034828092 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Amides - chemistry Amides - toxicity Anti-cancer drug Binding Sites Biological and medical sciences Cancer Cell Line, Tumor Cell Survival - drug effects Chaperones chemotypes Computer Simulation Crystallography, X-Ray Docking Drug Evaluation, Preclinical Evolution Fragments Heat shock protein 90 Hsp90 HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Humans Indazoles Indazoles - chemistry Ionizing radiation Medical sciences molecular chaperones Molecular weight Pharmacology. Drug treatments Protein Structure, Tertiary Small Molecule Libraries - chemistry Small Molecule Libraries - toxicity Structure-Activity Relationship Tumor cell lines X-radiation X-ray structure |
| title | Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T09%3A35%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fragment-based%20discovery%20of%20hydroxy-indazole-carboxamides%20as%20novel%20small%20molecule%20inhibitors%20of%20Hsp90&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Buchstaller,%20Hans-Peter&rft.date=2012-07-01&rft.volume=22&rft.issue=13&rft.spage=4396&rft.epage=4403&rft.pages=4396-4403&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2012.04.121&rft_dat=%3Cproquest_cross%3E1020830745%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1020830745&rft_id=info:pmid/22632933&rft_els_id=S0960894X1200580X&rfr_iscdi=true |