Kill Two Birds with One Stone: An Efficient and Potent AR CBS-Targeted Degrader Reverses Breast Cancer Resistance via Concurrent AR Degradation and ERα Transcriptional Suppression

The mechanism of endocrine resistance in breast cancer (BC) extends beyond <i>ESR1</i> mutations to include compensatory androgen receptor (AR) signaling. However, current therapeutic agents directed at the AR ligand-binding pocket (LBP) face the risk of failure due to mutations within this pocket. Herein, we reported a series of PROTACs targeting the AR coactivator binding site (AR-CBS) to overcome endocrine resistance in AR⁺ BC. Among which, degrader <b>18o</b> could not only effectively degrade AR, but also potently inhibit the proliferation of MCF-7 and multiple mutant or resistant BC cells. Simultaneously, <b>18o</b> effectively blocked estrogen receptor α (ERα) signaling through a dual mechanism involving ERα protein downregulation and suppression of its transcriptional activity. Importantly, <b>18o</b> exhibited excellent antitumor activity in both MCF-7 and LCC2 xenografted models. This proof-of-concept study confirms that AR-CBS is a promising target for BC treatment and highlights degrader <b>18o</b> as a potential candidate for overcoming the endocrine resistance.