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

Abstract

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.

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

“…Some PROTACs have been reported in the literature in relation to breast cancer therapy. ERD-308 is an ER degrader, which, compared to fulvestrant, showed a stronger inhibitory effect on proliferation in MCF-7 cells [ 13 ]. Small-molecule pan-BET degraders such as ARV-771 and dBET1 were designed to induce superior effects in breast cancer [ 14 , 15 ].…”

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

“… 18 , 19 Targets that have been shown to be degraded by PROTACs include members of bromodomain-containing proteins such as the BET proteins (Brd2, Brd3 and Brd4), 7 , 8 , 9 , 14 , 15 , 17 , 20 , 21 amongst other epigenetic protein classes; 22 , 23 , 24 , 25 , 26 protein kinases; 10 , 12 , 27 , 28 , 29 , 30 , 31 as well as non-bromodomain and non-kinase target proteins. 32 , 33 , 34 , 35 Recent progress in understanding principles of PROTAC mode of action, and demonstration of applicability across different target classes, suggest that PROTACs have the potential to target new protein families, including proteins that are difficult to block using current approaches. Clinical validation of small molecules inducing protein degradation is provided by recent discoveries on the molecular mechanism of thalidomide and related clinical anticancer immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which induce the proteasomal-dependent degradation of cancer-driving proteins.…”

PROTACs: great opportunities for academia and industry

“…In 2018, Wang and his colleagues disclosed a highly potent ER degrader called ERD-308 217 (Fig. 23).…”