The androgen receptor regulates androgen signalling through three domains: a ligand-binding domain (LBD), a DNA-binding domain (DBD) and the flexible amino-terminal domain (NTD), which makes up more than half of the protein. Hunter et al. have reviewed the NTD as an emerging therapeutic target in prostate cancer, particularly in advanced and drug-resistant disease.

Unlike the structured LBD and DBD, the NTD is intrinsically disordered, allowing dynamic folding, multiple protein–protein interactions and allosteric regulation. Structural studies using molecular modelling, nuclear magnetic resonance and cryo-electron microscopy have revealed helical regions within the NTD (TAU1 and TAU5), and its role in forming complexes with cofactors such as SRC-3, p300 and TFIIF. The NTD also contributes to liquid–liquid phase separation, forming condensates that may drive resistance to anti-androgen therapies. Novel drugs targeting the NTD include covalent inhibitors (EPI series, ET516, UT-143), reversible inhibitors (SC428, compound 16) and degraders or PROTACs (UT-34, Z15, BWA-522). These agents block androgen receptor signalling even in splice variants lacking the LBD.

Continued research aims to translate these findings into next-generation treatments for castration-resistant prostate cancer.

Read the full article in Endocrine Oncology https://doi.org/10.1530/EO-24-0061