Novel 11β-substituted estradiol conjugates: Transition from ERα agonizts to effective PROTAC degraders

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Endocrine therapy is a cornerstone of breast cancer treatment but often encounters drug resistance.
• Estrogen receptor alpha (ERα) signaling remains critical for the growth of many resistant breast cancers.

Purpose of the Study:

• To design, synthesize, and evaluate novel ERα-targeting PROTACs to overcome endocrine resistance.
• To identify potent small molecules that induce ERα degradation.

Main Methods:

• Synthesis of novel PROTACs by attaching E3 ligase ligands to estradiol at the 11β-position via linkers.
• Biological evaluation of PROTACs for ERα degradation activity and cell growth inhibition in MCF-7 cells.

Main Results:

• Identified potent ERα PROTAC 15b with excellent degradation activity (DC50 = 67 nM).
• PROTAC 15b demonstrated comparable cell growth inhibition to fulvestrant in MCF-7 cells.
• Compound 15b exhibited antagonistic effects in uterine cells and favorable physicochemical properties.

Conclusions:

• Novel ERα-targeting PROTACs are effective in degrading ERα and inhibiting breast cancer cell growth.
• PROTAC 15b is a promising lead compound for developing new anti-breast cancer agents to combat endocrine resistance.