Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer

Despite the development of highly effective therapies
for the treatment
of estrogen receptor α (ERα)-positive human breast cancer,
clinical resistance to current therapies requires the development
of novel therapeutic strategies. Herein, we report the discovery of
ERD-1233 as a potent and orally efficacious ERα degrader designed
using the PROTAC technology. ERD-1233 was developed based on Lasofoxifene
as the ER binding moiety and a novel cereblon ligand through extensive
optimization of the linker. ERD-1233 potently and effectively reduces
the ERα protein in vitro and achieves excellent oral bioavailability
in mice and rats. Oral administration of ERD-1233 effectively reduces
ER protein in ER+ tumors and achieves tumor regression in the ER wild-type
MCF-7 xenograft tumor model and strong tumor growth inhibition in
the ESR1Y537S mutated model in mice. Our
data demonstrate that ERD-1233 is a promising ER PROTAC degrader for
extensive evaluation as a new therapy for the treatment of ER+ human
breast cancer.