Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Estrogen receptor alpha (ERα) and aromatase (ARO) are key drivers in estrogen receptor-positive (ER+) breast cancer (BC) progression.
• Targeting ERα or estrogen synthesis via ARO is a standard treatment for ER+ BC.
• Endocrine resistance remains a significant challenge in BC management.

Purpose of the Study:

• To design and evaluate a novel class of dual-targeting Proteolysis Targeting Chimeras (PROTACs) against ERα and ARO.
• To assess the efficacy of a lead compound, 18c, in preclinical models of ER+ BC.
• To explore the potential of dual-targeting degraders in overcoming endocrine resistance.

Main Methods:

• Synthesis and characterization of dual-targeting PROTAC degraders.
• In vitro evaluation of compound 18c in ERα-positive breast cancer cell lines (MCF-7).
• In vivo efficacy studies using MCF-7 xenograft tumor models in mice.
• Assessment of activity against ERα-mutant (ERαMUT) cells.

Main Results:

• Compound 18c demonstrated potent dual degradation and inhibition of ERα and ARO.
• 18c effectively suppressed MCF-7 cell proliferation with minimal toxicity to normal cells.
• In vivo studies showed 18c inhibited tumor growth and promoted ERα/ARO degradation.
• 18c exhibited significant antiproliferative activity and ERα degradation in ERαMUT cells.

Conclusions:

• Compound 18c represents the first dual-targeting degrader for ERα and ARO.
• This novel therapeutic strategy shows significant potential for managing ER+ breast cancer.
• 18c offers a promising avenue for overcoming endocrine resistance in breast cancer treatment.