PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Estrogen receptor alpha (ERα) is crucial in breast cancer development and treatment.
• Resistance to current therapies often arises from mutations in ERα's ligand-binding domain (LBD).
• Targeting alternative domains like the DNA-binding domain (DBD) may circumvent resistance mechanisms.

Purpose of the Study:

• To design and evaluate a novel PROTAC targeting the ERα DBD.
• To assess the efficacy of this PROTAC in degrading ERα in breast cancer cells.
• To explore its potential in overcoming LBD-mediated drug resistance.

Main Methods:

• Design of a nucleic acid-conjugated PROTAC (ERE-PROTAC) utilizing a click reaction.
• Incorporation of an estrogen response element (ERE) sequence to recruit ERα via its DBD.
• Conjugation with VH032 to recruit the von Hippel-Lindau (VHL) E3 ligase.
• Assessment of ERα degradation in various breast cancer cell lines.

Main Results:

• ERE-PROTAC efficiently degraded ERα in breast cancer cells.
• The degradation was reversible, demonstrating controlled therapeutic potential.
• Targeting the ERα DBD with ERE-PROTAC showed effectiveness.
• The approach demonstrated potential to overcome resistance associated with ERα LBD mutations.

Conclusions:

• ERE-PROTAC represents a novel strategy for targeted protein degradation.
• Targeting the ERα DBD offers a promising avenue to overcome resistance in breast cancer therapy.
• This PROTAC technology holds potential for developing new breast cancer treatments.