title: AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.
abstract: 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.
authors.affiliation: Corresponding Author: A. Nigel Brooks, Oncology iMED, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. Nigel.Brooks@astrazeneca.com.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Loddick
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Ross
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Thomason
authors.forename: David M
authors.initials: DM
authors.lastname: Robinson
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Walker
authors.forename: Tom P J
authors.initials: TP
authors.lastname: Dunkley
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Brave
authors.forename: Nicola
authors.initials: N
authors.lastname: Broadbent
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Stratton
authors.forename: Dawn
authors.initials: D
authors.lastname: Trueman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mouchet
authors.forename: Fadhel S
authors.initials: FS
authors.lastname: Shaheen
authors.forename: Vivien N
authors.initials: VN
authors.lastname: Jacobs
authors.forename: Marie
authors.initials: M
authors.lastname: Cumberbatch
authors.forename: Joanne
authors.initials: J
authors.lastname: Wilson
authors.forename: Rhys D O
authors.initials: RD
authors.lastname: Jones
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: Alfred
authors.initials: A
authors.lastname: Rabow
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: A Nigel
authors.initials: AN
authors.lastname: Brooks
mesh_terms: D000069501:Abiraterone Acetate; D059002:Androgen Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012669:Seminal Vesicles / Q000187:drug effects* / Q000254:growth & development; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C583656:AZD3514; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011724:Pyridazines; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; D000069501:Abiraterone Acetate