Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

Area of Science:

• Molecular biology
• Endocrinology
• Drug discovery

Background:

• Steroid hormone receptors (SHRs) regulate gene expression via interactions with coregulatory proteins.
• Steroid receptor modulators (SRMs) bind to SHRs, inducing allosteric changes that affect target gene expression.
• Current SRMs primarily target the ligand-binding domain (LBD)/AF2, leading to limited selectivity and acquired resistance.

Purpose of the Study:

• To explore the therapeutic potential of targeting the intrinsically disordered (ID) N-terminal domain (NTD)/AF1 of SHRs.
• To review the role of allosteric regulation in modulating SHR activity, focusing on the AR's ID NTD/AF1.
• To highlight opportunities for developing novel therapeutics for prostate cancer by targeting AR's AF1 domain.

Main Methods:

• Review of existing literature on SHR structure, function, and therapeutic targeting.
• Analysis of studies investigating allosteric modulation of intrinsically disordered protein domains.
• Focus on androgen receptor (AR) as a model for targeting ID NTD/AF1 in castration-resistant prostate cancer.

Main Results:

• Intrinsically disordered NTD/AF1 domains offer unique allosteric modulation sites.
• Targeting AR's ID AF1 domain shows promise for castration-resistant prostate cancer therapy.
• Allosteric regulation of AR's structural dynamics, especially the ID NTD/AF1, is a key area for drug development.

Conclusions:

• Developing modulators targeting the NTD/AF1 domain can improve SHR therapeutic efficacy and selectivity.
• Exploiting allosteric regulation of AR's ID NTD/AF1 presents a promising avenue for prostate cancer drug development.
• Targeting structural flexibility and dynamics of ID NTD/AF1 domains is crucial for future therapeutic strategies.