BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients
Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wil...
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| Veröffentlicht in: | Oncotarget 2016-02, Vol.7 (5), p.6015-6028 |
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| creator | Sugawara, Tatsuo Lejeune, Pascale Köhr, Silke Neuhaus, Roland Faus, Hortensia Gelato, Kathy A Busemann, Matthias Cleve, Arwed Lücking, Ulrich von Nussbaum, Franz Brands, Michael Mumberg, Dominik Jung, Klaus Stephan, Carsten Haendler, Bernard |
| description | Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. |
| doi_str_mv | 10.18632/oncotarget.6864 |
| format | Article |
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Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.6864</identifier><identifier>PMID: 26760770</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Androgen Receptor Antagonists - pharmacology ; Animals ; Caco-2 Cells ; Cell Line, Tumor ; Chlorocebus aethiops ; COS Cells ; Down-Regulation ; Humans ; Male ; Mice ; Mice, SCID ; Mutation ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - metabolism ; Random Allocation ; Rats ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Research Paper ; Thiohydantoins - pharmacology ; Transfection ; Xenograft Model Antitumor Assays</subject><ispartof>Oncotarget, 2016-02, Vol.7 (5), p.6015-6028</ispartof><rights>Copyright: © 2016 Sugawara et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-d8a6690251d595c316dd8903df0b0e82430742ce9511640fcf71c56619190df33</citedby><cites>FETCH-LOGICAL-c420t-d8a6690251d595c316dd8903df0b0e82430742ce9511640fcf71c56619190df33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868737/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868737/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26760770$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sugawara, Tatsuo</creatorcontrib><creatorcontrib>Lejeune, Pascale</creatorcontrib><creatorcontrib>Köhr, Silke</creatorcontrib><creatorcontrib>Neuhaus, Roland</creatorcontrib><creatorcontrib>Faus, Hortensia</creatorcontrib><creatorcontrib>Gelato, Kathy A</creatorcontrib><creatorcontrib>Busemann, Matthias</creatorcontrib><creatorcontrib>Cleve, Arwed</creatorcontrib><creatorcontrib>Lücking, Ulrich</creatorcontrib><creatorcontrib>von Nussbaum, Franz</creatorcontrib><creatorcontrib>Brands, Michael</creatorcontrib><creatorcontrib>Mumberg, Dominik</creatorcontrib><creatorcontrib>Jung, Klaus</creatorcontrib><creatorcontrib>Stephan, Carsten</creatorcontrib><creatorcontrib>Haendler, Bernard</creatorcontrib><title>BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.</description><subject>Androgen Receptor Antagonists - pharmacology</subject><subject>Animals</subject><subject>Caco-2 Cells</subject><subject>Cell Line, Tumor</subject><subject>Chlorocebus aethiops</subject><subject>COS Cells</subject><subject>Down-Regulation</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Mutation</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - metabolism</subject><subject>Random Allocation</subject><subject>Rats</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Research Paper</subject><subject>Thiohydantoins - pharmacology</subject><subject>Transfection</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUTtLBDEQDqKo6PVWktJmNe9sGkHFFwg2WliFXJI9V_eSNckK_nuj53OaGfgeM8MHwB5Gh7gVlBzFYGMxaeHLoWgFWwPbWDHVEM7p-p95C8xyfkK1OJMtUZtgiwgpkJRoG9jTkweIEWFSSDgfon3O0ASX4sIHmLz1Y4kJLqdiQsmwi1NwsA_QmlySKX0MTfK5zx8wHFOsQ_EVDdYnOFaCr7JdsNGZIfvZV98B9xfnd2dXzc3t5fXZyU1jGUGlca0RQiHCseOKW4qFc61C1HVojnxLGEWSEesVx1gw1NlOYsuFwAor5DpKd8Dxynec5kvvbN2dzKDH1C9NetPR9Po_EvpHvYivmrWilVRWg4MvgxRfJp-LXvbZ-mEwwccpaywlx0ISzCsVrai2Pp2T737WYKQ_49G_8eiPeKpk_-95P4LvMOg748aO8A</recordid><startdate>20160202</startdate><enddate>20160202</enddate><creator>Sugawara, Tatsuo</creator><creator>Lejeune, Pascale</creator><creator>Köhr, Silke</creator><creator>Neuhaus, Roland</creator><creator>Faus, Hortensia</creator><creator>Gelato, Kathy A</creator><creator>Busemann, Matthias</creator><creator>Cleve, Arwed</creator><creator>Lücking, Ulrich</creator><creator>von Nussbaum, Franz</creator><creator>Brands, Michael</creator><creator>Mumberg, Dominik</creator><creator>Jung, Klaus</creator><creator>Stephan, Carsten</creator><creator>Haendler, Bernard</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160202</creationdate><title>BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients</title><author>Sugawara, Tatsuo ; Lejeune, Pascale ; Köhr, Silke ; Neuhaus, Roland ; Faus, Hortensia ; Gelato, Kathy A ; Busemann, Matthias ; Cleve, Arwed ; Lücking, Ulrich ; von Nussbaum, Franz ; Brands, Michael ; Mumberg, Dominik ; Jung, Klaus ; Stephan, Carsten ; Haendler, Bernard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-d8a6690251d595c316dd8903df0b0e82430742ce9511640fcf71c56619190df33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Androgen Receptor Antagonists - pharmacology</topic><topic>Animals</topic><topic>Caco-2 Cells</topic><topic>Cell Line, Tumor</topic><topic>Chlorocebus aethiops</topic><topic>COS Cells</topic><topic>Down-Regulation</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Mutation</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - metabolism</topic><topic>Random Allocation</topic><topic>Rats</topic><topic>Receptors, Androgen - genetics</topic><topic>Receptors, Androgen - metabolism</topic><topic>Research Paper</topic><topic>Thiohydantoins - pharmacology</topic><topic>Transfection</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>online_resources</toplevel><creatorcontrib>Sugawara, Tatsuo</creatorcontrib><creatorcontrib>Lejeune, Pascale</creatorcontrib><creatorcontrib>Köhr, Silke</creatorcontrib><creatorcontrib>Neuhaus, Roland</creatorcontrib><creatorcontrib>Faus, Hortensia</creatorcontrib><creatorcontrib>Gelato, Kathy A</creatorcontrib><creatorcontrib>Busemann, Matthias</creatorcontrib><creatorcontrib>Cleve, Arwed</creatorcontrib><creatorcontrib>Lücking, Ulrich</creatorcontrib><creatorcontrib>von Nussbaum, Franz</creatorcontrib><creatorcontrib>Brands, Michael</creatorcontrib><creatorcontrib>Mumberg, Dominik</creatorcontrib><creatorcontrib>Jung, Klaus</creatorcontrib><creatorcontrib>Stephan, Carsten</creatorcontrib><creatorcontrib>Haendler, Bernard</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sugawara, Tatsuo</au><au>Lejeune, Pascale</au><au>Köhr, Silke</au><au>Neuhaus, Roland</au><au>Faus, Hortensia</au><au>Gelato, Kathy A</au><au>Busemann, Matthias</au><au>Cleve, Arwed</au><au>Lücking, Ulrich</au><au>von Nussbaum, Franz</au><au>Brands, Michael</au><au>Mumberg, Dominik</au><au>Jung, Klaus</au><au>Stephan, Carsten</au><au>Haendler, Bernard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-02-02</date><risdate>2016</risdate><volume>7</volume><issue>5</issue><spage>6015</spage><epage>6028</epage><pages>6015-6028</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26760770</pmid><doi>10.18632/oncotarget.6864</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Androgen Receptor Antagonists - pharmacology Animals Caco-2 Cells Cell Line, Tumor Chlorocebus aethiops COS Cells Down-Regulation Humans Male Mice Mice, SCID Mutation Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - metabolism Random Allocation Rats Receptors, Androgen - genetics Receptors, Androgen - metabolism Research Paper Thiohydantoins - pharmacology Transfection Xenograft Model Antitumor Assays |
| title | BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients |
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