PO.EN01.01 · 内分泌肿瘤
一种口服生物利用的AR-NTD降解剂，可绕过LBD依赖性耐药并防止晚期前列腺癌中AR-V7介导的反馈
An orally bioavailable AR-NTD degrader that bypasses LBD-dependent resistance and prevents AR-V7-mediated feedback in advanced prostate cancer
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摘要 Abstract
中文摘要
在去势抵抗性前列腺癌（CRPC）中，对第二代抗雄激素药物的耐药性通常由雄激素受体（AR）剪接变体（如AR-V7）驱动，这些变体缺乏配体结合结构域（LBD）并逃避现有疗法。为应对这一未满足的需求，我们研发了ITRI-148，一种口服生物利用的PROTAC，靶向AR的N端结构域（NTD），诱导全长AR和AR剪接变体的降解。基于结构的建模确定了AR-NTD内一个可成药口袋，可容纳ITRI-148，从而募集cereblon（CRBN）并形成有效的三元复合物。邻近连接分析证实了AR-CRBN相互作用，导致AR、AR-V7以及临床相关耐药突变体的选择性蛋白酶体降解。全局蛋白质组学分析显示出高靶点选择性，AR为主要降解蛋白。在恩杂鲁胺耐药的C4-2B/MDVR细胞中，ITRI-148相比恩杂鲁胺和靶向LBD的降解剂ARV-110展示出更优的抗增殖活性。值得注意的是，长期恩杂鲁胺治疗诱导AR-V7上调和PSA反弹，而ITRI-148维持了对AR信号传导的持久抑制，且不触发适应性耐药。在体内，口服ITRI-148在去势VCaP异种移植中诱导显著的肿瘤消退，并抑制激素完整的CWR22Rv1模型的肿瘤生长。大鼠毒代动力学研究显示，在治疗剂量下具有良好的全身暴露，无显著体重下降或血液学毒性。总体而言，这些发现确立了ITRI-148作为一种泛AR降解剂，可绕过LBD依赖性耐药机制并防止AR-V7介导的反馈，支持其作为晚期CRPC下一代疗法的潜力。
查看英文原文 English 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.
利益披露 Disclosure
L. Wang, None..
C. Hung, None..
W. Hsu, None..
T. Wang, None.