AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization...
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| Veröffentlicht in: | Molecular cancer therapeutics 2013-09, Vol.12 (9), p.1715-1727 |
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| creator | Loddick, Sarah A Ross, Sarah J Thomason, Andrew G Robinson, David M Walker, Graeme E Dunkley, Tom P J Brave, Sandra R Broadbent, Nicola Stratton, Natalie C Trueman, Dawn Mouchet, Elizabeth Shaheen, Fadhel S Jacobs, Vivien N Cumberbatch, Marie Wilson, Joanne Jones, Rhys D O Bradbury, Robert H Rabow, Alfred Gaughan, Luke Womack, Chris Barry, Simon T Robson, Craig N Critchlow, Susan E Wedge, Stephen R Brooks, A Nigel |
| description | Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation. |
| doi_str_mv | 10.1158/1535-7163.MCT-12-1174 |
| format | Article |
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AZD3514 is currently in phase I clinical evaluation.</description><subject>Abiraterone Acetate</subject><subject>Androgen Receptor Antagonists - metabolism</subject><subject>Androgen Receptor Antagonists - pharmacology</subject><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Phenylthiohydantoin - analogs & derivatives</subject><subject>Phenylthiohydantoin - pharmacology</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Pyridazines - chemical synthesis</subject><subject>Pyridazines - metabolism</subject><subject>Pyridazines - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Seminal Vesicles - drug effects</subject><subject>Seminal Vesicles - growth & development</subject><subject>Signal Transduction - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1DAQtRCIfsBPAPnIJcVjJ7bDAanaQkEq4lIuXCzHcbauHHuxnZX673F22wpO9sy89-ZpHkLvgFwAdPIjdKxrBHB28WNz2wBtAET7Ap3WvmxkB-3Lw_-IOUFnOd8TArKn8BqdUCY5sFacouny9xWr6E9Y4zxr7_EcvTWLt7jc6VKrcfG62Ix1GFPc2oCTNXZXYsLZbYP2LmzXGZ6WYIqLAbuA966keOgein18g15N2mf79vE9R7--frndfGtufl5_31zeNKYFKE07VLfcyrabSN-P1f8Iggg5gBRG99xoRvueWionQwwjIzOib_kwVB6VvGPn6PNRd7cMsx2NDSVpr3bJzTo9qKid-n8S3J3axr1igveUiCrw4VEgxT-LzUXNLhvrvQ42LllBy4D2XEpeod0RalLMOdnpeQ0QtWak1vur9f6qZqSAqjWjynv_r8dn1lMo7C_lvo2o</recordid><startdate>20130901</startdate><enddate>20130901</enddate><creator>Loddick, Sarah A</creator><creator>Ross, Sarah J</creator><creator>Thomason, Andrew G</creator><creator>Robinson, David M</creator><creator>Walker, Graeme E</creator><creator>Dunkley, Tom P J</creator><creator>Brave, Sandra R</creator><creator>Broadbent, Nicola</creator><creator>Stratton, Natalie C</creator><creator>Trueman, Dawn</creator><creator>Mouchet, Elizabeth</creator><creator>Shaheen, Fadhel S</creator><creator>Jacobs, Vivien N</creator><creator>Cumberbatch, Marie</creator><creator>Wilson, Joanne</creator><creator>Jones, Rhys D O</creator><creator>Bradbury, Robert H</creator><creator>Rabow, Alfred</creator><creator>Gaughan, Luke</creator><creator>Womack, Chris</creator><creator>Barry, Simon T</creator><creator>Robson, Craig N</creator><creator>Critchlow, Susan E</creator><creator>Wedge, Stephen R</creator><creator>Brooks, A Nigel</creator><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>20130901</creationdate><title>AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo</title><author>Loddick, Sarah A ; Ross, Sarah J ; Thomason, Andrew G ; Robinson, David M ; Walker, Graeme E ; Dunkley, Tom P J ; Brave, Sandra R ; Broadbent, Nicola ; Stratton, Natalie C ; Trueman, Dawn ; Mouchet, Elizabeth ; Shaheen, Fadhel S ; Jacobs, Vivien N ; Cumberbatch, Marie ; Wilson, Joanne ; Jones, Rhys D O ; Bradbury, Robert H ; Rabow, Alfred ; Gaughan, Luke ; Womack, Chris ; Barry, Simon T ; Robson, Craig N ; Critchlow, Susan E ; Wedge, Stephen R ; Brooks, A Nigel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-4b7166e845f099d153d17078b187ca96ca32992e28fc0c30d3c7946bbb7128653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Abiraterone Acetate</topic><topic>Androgen Receptor Antagonists - 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| ispartof | Molecular cancer therapeutics, 2013-09, Vol.12 (9), p.1715-1727 |
| issn | 1535-7163 1538-8514 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Abiraterone Acetate Androgen Receptor Antagonists - metabolism Androgen Receptor Antagonists - pharmacology Androstadienes - pharmacology Animals Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Cell Line, Tumor Disease Models, Animal Down-Regulation Drug Screening Assays, Antitumor Gene Expression Regulation, Neoplastic HCT116 Cells Humans Male Mice Mice, Nude Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - pharmacology Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - pathology Pyridazines - chemical synthesis Pyridazines - metabolism Pyridazines - pharmacology Rats Rats, Wistar Receptors, Androgen - genetics Receptors, Androgen - metabolism Seminal Vesicles - drug effects Seminal Vesicles - growth & development Signal Transduction - drug effects Xenograft Model Antitumor Assays |
| title | AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo |
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