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 <b>BY13</b> 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, <b>BY13</b> 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 <b>BY13</b> as a lead compound for developing novel therapeutics to overcome endocrine resistance in breast cancer.