Drug Development Focused on the N-terminal Domain
The EPI compounds represent a new class of drugs that block a novel target on the androgen receptor (AR), the N-terminal domain. The N-terminal domain controls the transcriptional activity of the AR. This domain is critical for AR function and is not currently targeted by any other therapy.
The Current Problem
Current hormonal therapies work by either depleting levels of androgen, inhibiting the synthesis of androgens, or by preventing androgen from binding to the AR. However, prolonged treatment to current therapies can render cancer resistant to existing therapies over time.
The development of resistance can involve a multitude of mechanisms, however these commonly involve the development of mutations or truncations in the AR ligand-binding domain, allowing the AR to remain active. By targeting a different segment of the AR, the N-terminal domain, EPI compounds may bypass these resistance mechanisms.
Getting to the Root of the Problem
The EPI compounds work differently from current hormonal therapies because they target the N-terminal domain of the AR, a domain that is critical for AR transcriptional activity. Specifically, EPI prevents binding of transcriptional activator proteins to the AR N-terminal, inhibiting AR-mediated transcriptional activity.