一种首创的TAU-1定向的雄激素受体（AR）和AR-V7降解剂，募集DDB1-CUL4-RBX1 E3连接酶以消除致死性前列腺癌中的AR信号

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease driven by persistent androgen receptor (AR) signaling despite androgen deprivation and next-generation AR pathway inhibitors. Ligand-independent AR splice variants, most notably AR-V7, are expressed in approximately 75% of mCRPC cases and confer resistance to standard-of-care therapies. Because AR-V7 lacks the ligand-binding domain no selective pharmacologic inhibitors exist, representing an unmet clinical need. Here, we report a first-in-field, TAU-1-directed N-terminal AR degrader that induces coordinated proteasomal elimination of both AR and AR-V7. Through a high-throughput phenotypic screen of ~170,000 compounds, we identified a novel chemotype capable of degrading both AR species. Medicinal chemistry-driven structure-activity relationship studies yielded compound #15, a potent and selective small molecule that rapidly induces AR-fl and AR-V7 degradation. Using domain-based AR and AR-V7 constructs, compound #15 selectively promoted degradation of N-terminal domain-containing AR fragments, mapping activity to the TAU-1 subdomain within the AR activation function-1 (AF-1). Functionally, compound #15 induced rapid Cullin-RING ligase-dependent ubiquitination and degradation of AR/AR-V7 within 3 hours, an effect fully blocked by proteasome inhibition or by inhibition of cullin neddylation with MLN4924. To define the E3 ubiquitin ligase machinery mediating AR/AR-V7 degradation, we performed a focused CRISPR-Cas9 loss-of-function screen targeting E3 ligases and associated adaptors. This screen identified DDB1, CUL4, and RBX1 as top resistance hits whose depletion rescued AR-fl and AR-V7 protein levels in the presence of compound #15. Genetic ablation of DDB1 abrogated compound-induced AR-V7 and AR-fl degradation, indicating a required role for DDB1 in substrate recognition, which is consistent with prior molecular glue-like mechanisms. This defined E3 dependency, together with rapid proteasome-dependent target loss, is consistent with a molecular glue-like degradation mechanism and distinguishes compound #15 from existing AR-targeting strategies. In contrast to previously reported N-terminal AR degraders that work through the TAU-5 subdomain, this study establishes TAU-1 as a distinct and sufficient degradation-competent node within the AR N-terminus and represents the first report of TAU-1-mediated degradation of both AR-fl and AR-V7. By targeting a shared N-terminal vulnerability, this strategy enables suppression of ligand-dependent and ligand-independent AR signaling, in a single treatment, and offers a therapeutic paradigm with the potential to overcome resistance mechanisms. Ongoing studies are defining the structure of the TAU-1-AR-DDB1-CUL4 ternary complex to enable structure-guided optimization of this first-in-class molecular glue degrader.