Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer.
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.
['Dalal|Kush|K|', 'Roshan-Moniri|Mani|M|', 'Sharma|Aishwariya|A|', 'Li|Huifang|H|', 'Ban|Fuqiang|F|', 'Hessein|Mohamed|M|', 'Hsing|Michael|M|', 'Singh|Kriti|K|', 'LeBlanc|Eric|E|', 'Dehm|Scott|S|', 'Tomlinson Guns|Emma S|ES|', 'Cherkasov|Artem|A|', 'Rennie|Paul S|PS|']
D021581:Active Transport, Cell Nucleus D000595:Amino Acid Sequence D059002:Androgen Receptor Antagonists D000818:Animals D001665:Binding Sites D002467:Cell Nucleus D002843:Chromatin D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007093:Imidazoles D061986:MCF-7 Cells D008297:Male D008819:Mice, Nude D008969:Molecular Sequence Data D058990:Molecular Targeted Therapy D011471:Prostatic Neoplasms D011485:Protein Binding D020033:Protein Isoforms D011944:Receptors, Androgen D013844:Thiazoles D014158:Transcription, Genetic D015533:Transcriptional Activation D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
Androgen Receptor Prostate Cancer DNA-binding Protein Drug Discovery Nuclear Receptor