Androgen receptor modulators: a review of recent patents and reports (2012-2018)

ABSTRACT

Introduction: Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD).

Areas covered: The authors provide an overview of AR-modulating agents from 2012 to 2018.

Expert opinion: The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.

KEYWORDS:

• Androgen receptor
• nuclear receptor
• antiandrogen
• SARM

Article highlights

• This review provides an overview and analysis of AR modulators patented between 2012 and 2018.

• Current AR modulators include conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional transcription inhibitors.

• Targets for next-generation androgen modulators will include not only the ligand-binding domain, but also the N-terminal or the DNA-binding domain, or even other sites.

• Development of tactics to modulate each of the functional domains of AR should yield multiple and synergistic strategies to treat any kind of androgen-dependent condition.

This box summarizes key points contained in the article.

Declaration of interest

S Fujii was employee of Tokyo Medical and Dental University and H Kagechika is employee of Tokyo Medical and Dental University.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.