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, CP03 displayed potent and selective ERα degradation and antiproliferative
effects in multiple BC cell lines with wild-type or mutant ERα. In vivo, CP03 exhibited excellent antitumor
and ERα degradation activity in MCF-7 and drug-resistant LCC-2
xenografted models. These findings demonstrated that CP03 may offer a novel degradation strategy to overcome endocrine resistance,
providing new opportunities for the development of innovative treatments
for ERα+ BC.