Abstract Resistance to second-generation antiandrogens in castration-resistant prostate cancer (CRPC) is frequently driven by androgen receptor (AR) splice variants such as AR-V7, which lack the ligand-binding domain (LBD) and evade current therapies. To address this unmet need, we developed ITRI-148, an orally bioavailable PROTAC that targets the AR N-terminal domain (NTD) to induce degradation of both full-length AR and AR splice variants. Structure-guided modeling identified a druggable pocket within the AR-NTD that accommodates ITRI-148, enabling recruitment of cereblon (CRBN) and formation of a productive ternary complex. Proximity ligation assays confirmed AR-CRBN interaction, leading to selective proteasomal degradation of AR, AR-V7, and clinically relevant resistant mutants. Global proteomic profiling demonstrated high target selectivity, with AR as the primary degraded protein. In enzalutamide-resistant C4-2B/MDVR cells, ITRI-148 exhibited superior antiproliferative activity compared with enzalutamide and the LBD-targeted degrader ARV-110. Notably, long-term enzalutamide treatment induced AR-V7 upregulation and PSA rebound, whereas ITRI-148 maintained durable suppression of AR signaling without triggering adaptive resistance. In vivo, oral ITRI-148 induced significant tumor regression in castrated VCaP xenografts and inhibited tumor growth in hormone-intact CWR22Rv1 models. Toxicokinetic studies in rats showed favorable systemic exposure without significant body weight loss or hematologic toxicity at therapeutic doses. Collectively, these findings establish ITRI-148 as a pan-AR degrader that bypasses LBD-dependent resistance mechanisms and prevents AR-V7-mediated feedback, supporting its potential as a next-generation therapy for advanced CRPC. Citation Format: Ling-Yu Wang, Chiu-Lien Hung, Wen-Ning Hsu, Tsan-Chun Wang. An orally bioavailable AR-NTD degrader that bypasses LBD-dependent resistance and prevents AR-V7-mediated feedback in advanced prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB112.
Wang et al. (Fri,) studied this question.