Androgen receptor N-terminal domain (AR-NTD) (AR-NTD)

The Androgen receptor N-terminal domain (AR-NTD) is a large, intrinsically disordered region of the androgen receptor (AR) that contains the primary transactivation function, known as Activation Function 1 (AF-1) [1, 2]. Unlike the C-terminal ligand-binding domain (LBD) targeted by conventional anti-androgens, the NTD is essential for the transcriptional activity of both the full-length AR and its truncated splice variants, such as AR-V7, which are frequently implicated in castration-resistant prostate cancer (CRPC) [3, 4]. Because these splice variants lack the LBD, they are constitutively active and resistant to standard therapies like enzalutamide or abiraterone [4]. Targeting the AR-NTD offers a therapeutic strategy to bypass LBD-driven resistance by directly inhibiting the receptor's ability to recruit co-activators and initiate gene transcription [2, 5]. Current drug development focuses on small molecules, such as EPI-7386, that bind to specific motifs within the NTD to disrupt these critical protein-protein interactions [4, 5]. This approach is particularly relevant for patients who have developed resistance to second-generation anti-androgens and exhibit AR-driven disease progression [5].

Other names

Activation Function 1 (AF-1)N-terminal transactivation domainTau-1Tau-5AR-NTD

Inhibition of the androgen receptor N-terminal domain (AR-NTD) by small molecules that bind to the Activation Function 1 (AF-1) region, thereby preventing the recruitment of transcriptional co-activators and blocking the assembly of the transcription initiation complex [2, 4]. This mechanism effectively inhibits the transcriptional activity of both full-length androgen receptor and constitutively active splice variants (e.g., AR-V7) that lack the ligand-binding domain [3, 4].