Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)

The
estrogen receptor (ER) is a validated target for the treatment
of estrogen receptor-positive (ER+) breast cancer. Here, we describe
the design, synthesis, and extensive structure–activity relationship
(SAR) studies of small-molecule ERα degraders based on the proteolysis
targeting chimeras (PROTAC) concept. Our efforts have resulted in
the discovery of highly potent and effective PROTAC ER degraders,
as exemplified by ERD-308 (32). ERD-308 achieves DC50 (concentration causing 50% of protein degradation) values
of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines,
respectively, and induces >95% of ER degradation at concentrations
as low as 5 nM in both cell lines. Significantly, ERD-308 induces
more complete ER degradation than fulvestrant, the only approved selective
ER degrader (SERD), and is more effective in inhibition of cell proliferation
than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may
lead to a new therapy for advanced ER+ breast cancer.