Androgen receptor N-terminal domain (AF-1 region) (AR-NTD (AF-1))

The Androgen receptor N-terminal domain (AR-NTD), specifically the Activation Function 1 (AF-1) region, is the primary driver of the receptor's transcriptional activity (UniProt P10275). It is an intrinsically disordered region (IDR) that facilitates the recruitment of coregulators and the general transcription machinery to androgen-responsive elements in the genome (PubMed: 21441306). In advanced prostate cancer, particularly castration-resistant prostate cancer (CRPC), the AR often becomes hypersensitive or undergoes splicing (e.g., AR-V7) that removes the C-terminal ligand-binding domain (LBD), rendering traditional anti-androgens ineffective (PubMed: 26011655). Because the AF-1 region remains present and functional in these variants, it has emerged as a vital therapeutic target. Drugs like EPI-7386 are designed to bind this region and inhibit AR-mediated gene transcription regardless of the presence of androgens or the LBD (PubMed: 32814664). This approach offers a potential solution to overcome resistance in patients who have failed standard-of-care hormonal therapies. Beyond cancer, mutations in the AR-NTD are associated with androgen insensitivity syndromes and neuromuscular disorders like spinal and bulbar muscular atrophy (UniProt P10275).

Other names

Activation Function 1AF-1Tau-1Tau-5AR-NTDN-terminal transactivation domain

Small molecule inhibitors bind to the intrinsically disordered N-terminal domain, specifically the AF-1 region, to block protein-protein interactions and inhibit the transcriptional activity of the androgen receptor, including constitutively active splice variants (PubMed: 26011655, PubMed: 32814664).