2. Academic Validation
  3. 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

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

  • J Med Chem. 2025 Jun 12;68(11):11516-11542. doi: 10.1021/acs.jmedchem.5c00425.
Jinsen Liang 1,  Dandan Wang 2,  Yihe Wu 2,  Jiahao Shi 2,  Baohua Xie 2,  Ruijing Xiao 2,  Jian Ni 2,  Chao Wang 2,  Chune Dong 2,  Hong-Bing Shu 1,  Shu Li 1,  Hai-Bing Zhou 1 2 3
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University; Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 State Key Laboratory of Virology and Biosafety, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
PMID: 40434408 DOI: 10.1021/acs.jmedchem.5c00425
Abstract

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.

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