Intercepting the Downstream of the Estrogen Receptor Signaling Pathway: Discovery of a Potent and Efficient SRC‑3 PROTAC Degrader for Overcoming Endocrine Resistance Breast Cancer

The
oncogene steroid receptor coactivator-3 (SRC-3) plays
a pivotal
role in the downstream transcriptional regulation mediated by the
estrogen receptor (ER), thereby promoting the occurrence and progression
of endocrine resistance in breast cancer. Herein, we disclose a novel
series of potent SRC-3 PROTACs to overcome endocrine resistance. These
PROTACs were able to efficiently degrade SRC-3 and inhibit the proliferation
of wild-type and endocrine-resistant breast cancer cells. Notably,
compound BY13 could significantly inhibit the growth
of drug-resistant breast tumors without observed toxicity in mice.
Mechanism studies indicated that the degradation ability of these
SRC-3 PROTAC degraders is ubiquitin proteasome system (UPS) pathway-dependent.
Moreover, BY13 displays a highly selective blocking effect
on the ER signaling pathway over that of the androgen receptor. This
proof-of-concept study firmly confirms that SRC-3 is a promising therapeutic
target for breast cancer treatment and highlights BY13 as a lead compound for developing novel therapeutics to overcome
endocrine resistance in breast cancer.