Oral bioavailable ITRI-148 degrades androgen receptor variants and overcomes antiandrogen resistance in advanced prostate cancer.

Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer (CRPC), with AR splice variants like AR-V7 contributing to resistance against second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) provides a strategy to bypass ligand-binding domain (LBD)-mediated resistance. We developed ITRI-148, a CRBN-based AR-NTD degrader incorporating a rigid piperidine-alkyne linker optimized for oral pharmacokinetics. ITRI-148 efficiently degrades full-length AR, AR-V7, and clinically relevant mutants (L702H, H875Y). It facilitates the recruitment of active AR species to CRBN in the nucleus, promoting their polyubiquitination and proteasomal degradation. In CRPC and enzalutamide-resistant models, ITRI-148 robustly suppresses AR signaling and inhibits cell viability, outperforming enzalutamide. With long-term treatment, it achieves sustained AR suppression without inducing compensatory AR-V7 upregulation or PSA re-expression. In vivo, ITRI-148 demonstrates potent antitumor efficacy in both castrated and hormone-intact CRPC models, supported by favorable pharmacokinetic properties, stability and safety profiles. These findings position ITRI-148 as a promising next-generation AR-targeting agent capable of degrading resistant AR variants and providing durable inhibition of AR signaling in advanced prostate cancer.