title: Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer.
abstract: The androgen receptor (AR) is a transcription factor that has a pivotal role in the occurrence and progression of prostate cancer. The AR is activated by androgens that bind to its ligand-binding domain (LBD), causing the transcription factor to enter the nucleus and interact with genes via its conserved DNA-binding domain (DBD). Treatment for prostate cancer involves reducing androgen production or using anti-androgen drugs to block the interaction of hormones with the AR-LBD. Eventually the disease changes into a castration-resistant form of PCa where LBD mutations render anti-androgens ineffective or where constitutively active AR splice variants, lacking the LBD, become overexpressed. Recently, we identified a surfaced exposed pocket on the AR-DBD as an alternative drug-target site for AR inhibition. Here, we demonstrate that small molecules designed to selectively bind the pocket effectively block transcriptional activity of full-length and splice variant AR forms at low to sub-micromolar concentrations. The inhibition is lost when residues involved in drug interactions are mutated. Furthermore, the compounds did not impede nuclear localization of the AR and blocked interactions with chromatin, indicating the interference of DNA binding with the nuclear form of the transcription factor. Finally, we demonstrate the inhibition of gene expression and tumor volume in mouse xenografts. Our results indicate that the AR-DBD has a surface site that can be targeted to inhibit all forms of the AR, including enzalutamide-resistant and constitutively active splice variants and thus may serve as a potential avenue for the treatment of recurrent and metastatic prostate cancer.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and. Electronic address: kdalal@prostatecentre.com.
authors.forename: Kush
authors.initials: K
authors.lastname: Dalal
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Mani
authors.initials: M
authors.lastname: Roshan-Moniri
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Aishwariya
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hessein
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsing
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Kriti
authors.initials: K
authors.lastname: Singh
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Eric
authors.initials: E
authors.lastname: LeBlanc
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Scott
authors.initials: S
authors.lastname: Dehm
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Tomlinson Guns
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada and.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D011944:Receptors, Androgen / Q000737:chemistry / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000594847:4-(4-(4,5-bromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine; D059002:Androgen Receptor Antagonists; D002843:Chromatin; D007093:Imidazoles; D020033:Protein Isoforms; D011944:Receptors, Androgen; D013844:Thiazoles
keywords: Androgen Receptor; DNA-binding Protein; Drug Discovery; Nuclear Receptor; Prostate Cancer
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