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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Estrogen receptor alpha (ERα) signaling is a key target for ERα-positive breast cancer (ERα+ BC) therapy.
• Intrinsic and acquired resistance to endocrine therapies presents a major clinical challenge.
• Targeting the ERα coactivator binding site (CBS) offers an alternative to overcome resistance mechanisms associated with ligand binding domain (LBD) mutations.

Purpose of the Study:

• To develop novel Proteolysis-Targeting Chimeras (PROTACs) that target the unconventional coactivator binding site (CBS) of ERα.
• To evaluate the efficacy of these PROTACs in degrading ERα and inhibiting proliferation in ERα+ BC models.
• To assess the therapeutic potential of CP03 in overcoming endocrine resistance.

Main Methods:

• Design and synthesis of first-in-class PROTACs targeting ERα CBS.
• In vitro evaluation of ERα degradation and antiproliferative activity in ERα+ BC cell lines (wild-type and mutant ERα).
• In vivo assessment of antitumor and ERα degradation activity in xenografted mouse models (MCF-7 and drug-resistant LCC-2).

Main Results:

• CP03 demonstrated potent and selective degradation of ERα.
• CP03 exhibited significant antiproliferative effects across various ERα+ BC cell lines.
• CP03 showed excellent in vivo antitumor activity and ERα degradation in both sensitive and resistant xenograft models.

Conclusions:

• CP03 represents a novel PROTAC-based strategy for ERα degradation.
• This approach holds promise for overcoming endocrine resistance in ERα+ BC.
• CP03 offers new therapeutic opportunities for patients with ERα+ breast cancer, particularly those resistant to conventional therapies.