While anti-androgen therapies offer initial benefits, resistance frequently develops, leading to castration-resistant prostate cancer (CRPC).
Notably, the emergence of AR splice variants, particularly AR-V7, lacking the ligand-binding domain (LBD), presents a significant challenge in CRPC treatment.

Existing AR-targeting PROTACs primarily focus on the LBD, rendering them ineffective against AR-V7. This highlights a critical need for novel therapies that can effectively target AR-V7 and overcome resistance mechanisms.
In a recent study, researchers reported the development of NP18, a highly potent, non-covalent PROTAC that targets the N-terminal domain (NTD) of AR. NP18 effectively degrades both full-length AR (AR-FL) and AR-V7, exhibiting promising antitumor activity in preclinical models, including patient-derived xenograft (PDX) models.

NP18’s unique mechanism of action, targeting the NTD shared by various AR forms, offers a significant advantage.

This approach allows for the simultaneous inhibition of all clinically relevant AR variants, including AR-FL, AR mutants, and AR-V7. Importantly, NP18 demonstrates superior antitumor activity compared to the NTD antagonist EPI-002, from which it was derived.
The development of NP18 represents a significant breakthrough in prostate cancer treatment, particularly for CRPC patients with AR splice variants. This first-in-class, non-covalent PROTAC targeting the intrinsically disordered NTD of AR offers a promising strategy to address the unmet clinical need for effective therapies against AR-V7-driven resistance.

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