Prostate cancer is the second most frequently diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Although androgen receptor (AR)–targeted therapies such as enzalutamide improve patient outcomes, acquired resistance frequently leads to castration-resistant prostate cancer (CRPC) and metastatic CRPC (mCRPC). Therefore, strategies capable of eliminating AR signaling in resistant tumors remain an urgent medical need.

Here, we report AR-targeting autophagosome-tethering compounds (AR-ATTECs), a novel class of degraders that induce selective AR degradation via the LC3-mediated autophagy–lysosome pathway. Unlike PROTACs, ATTECs recruit target proteins to autophagic machinery for ubiquitination-independent lysosomal degradation.

Approximately 1,800 AR-ATTEC candidates were designed by combining LC3-binding ligands, linker structures, and AR-targeting moieties. Selected compounds were synthesized and evaluated in prostate cancer models. In androgen-dependent LNCaP cells, AR-ATTECs induced robust AR degradation with strong antiproliferative effects.

Importantly, optimized AR-ATTECs retained potent activity in enzalutamide-resistant VCaP cells (VCaP-EnzR), showing strong antiproliferative efficacy (GI50 = 16–950 nM) and efficient AR degradation (DC50 = 0.4–10 nM). These findings demonstrate that AR-ATTECs overcome enzalutamide resistance through autophagy-dependent AR degradation and represent a promising strategy for resistant prostate cancer.