title: Engineered repressors are potent inhibitors of androgen receptor activity.
abstract: Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These 'engineered repressors' are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
authors.affiliation: Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, W12 0NN, UK.
authors.forename: Greg N
authors.initials: GN
authors.lastname: Brooke
authors.forename: Sue M
authors.initials: SM
authors.lastname: Powell
authors.forename: Derek N
authors.initials: DN
authors.lastname: Lavery
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Bevan
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015202:Protein Engineering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins