Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)

Inhibition of estrogen receptor alpha (ERα) signaling
is
an established therapeutic approach for the treatment of ER-positive
(ER+) breast cancers, but new therapeutic strategies are urgently
needed to overcome clinical resistance. In the present study, we describe
the discovery and extensive evaluation of ERD-12310A as an exceptionally
potent and orally efficacious PROTAC degrader of ERα. ERD-12310A
achieved a DC50 value of 47 pM and is 10 times more potent
than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile
in mice and rats over ARV-471. ERD-12310A attained tumor regression
in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model
with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A
achieved strong tumor growth inhibition in MCF-7 xenograft tumors
harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens.
Our data position ERD-12310A as a promising candidate for further
development as a potential therapy for ER+ breast cancer.