Targeted Degradation of the Estrogen Receptor α through Unconventional Coactivator Binding Site (CBS)

Inhibiting the estrogen receptor α (ERα) signaling axis constitutes a fundamental approach in therapy for ERα-positive breast cancer (ERα⁺ BC). However, the emergence of intrinsic and acquired resistance to endocrine therapies poses a significant challenge. Alternatively, targeting the coactivator binding site (CBS) of ERα instead of the conventional ligand binding domain (LBD) may directly disrupt the ERα transcription process, thereby circumventing resistance associated with LBD mutations. Herein, we report the development of first-in-class PROTACs targeting the unconventional coactivator binding site (CBS) of ERα. Among them, <b>CP03</b> displayed potent and selective ERα degradation and antiproliferative effects in multiple BC cell lines with wild-type or mutant ERα. <i>In vivo</i>, <b>CP03</b> exhibited excellent antitumor and ERα degradation activity in MCF-7 and drug-resistant LCC-2 xenografted models. These findings demonstrated that <b>CP03</b> may offer a novel degradation strategy to overcome endocrine resistance, providing new opportunities for the development of innovative treatments for ERα⁺ BC.