Targeting the Androgen Receptor and Associated Cofactors in Prostate Cancer: Novel Approaches and Future Perspectives

Following the first approval for prostate cancer (PCa) treatment of competitive antagonists of the androgen receptor (AR) function that bind to the androgen-binding pocket, much progress has been achieved regarding compound efficacy and specificity. Second-generation compounds and androgen synthesis blockers are now standard-of-care AR pathway inhibitors given to PCa patients. More recently, approaches targeting AR regions other than the ligand-binding domain (LBD), stimulating proteasome-mediated AR degradation, or bringing together the AR with an effector protein (EP) in prostate tumor cells, have been explored and, in several cases, clinically tested. Compounds blocking AR mRNA splicing or directly addressing AR splice variants, especially the constitutively active AR-V7 form, are also being evaluated. In addition, there are ongoing efforts aiming at impairing the function of essential AR cofactors, mainly those involved in downstream gene transcription and chromatin modulation. Alternative techniques to impair AR activity, such as nanoparticle formulations and targeting biomolecular condensates are furthermore being explored. Here we present the most recent developments in these different strategies to target the AR, directly or indirectly, for a more potent and long-lasting blockade. This will hopefully soon lead to treatments that improve progression-free and overall survival in PCa patients, while maintaining a good safety profile.