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

2019; American Chemical Society; Volume: 62; Issue: 3 Linguagem: Inglês

10.1021/acs.jmedchem.8b01572

1520-4804

Jiantao Hu, Biao Hu, Mingliang Wang, Fuming Xu, Bukeyan Miao, Chao‐Yie Yang, Mi Wang, Zhaomin Liu, Daniel F. Hayes, Krishnapriya Chinnaswamy, James Delproposto, Jeanne A. Stuckey, Shaomeng Wang,

Multiple Myeloma Research and Treatments

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.