2. Academic Validation
  3. Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

  • J Med Chem. 2024 Jun 13;67(11):8913-8931. doi: 10.1021/acs.jmedchem.4c00196.
Lilan Xin 1,  Chao Wang 1,  Yan Cheng 1,  Hongli Wang 1,  Xinyi Guo 1,  Xiaofei Deng 1,  Xiangping Deng 1,  Baohua Xie 1,  Hankun Hu 2,  Chang Min 1,  Chune Dong 1,  Hai-Bing Zhou 1 3
Affiliations

Affiliations

  • 1 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, 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, Wuhan University, Wuhan 430071, China.
PMID: 38809993 DOI: 10.1021/acs.jmedchem.4c00196
Abstract

Estrogen Receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast Cancer (BC) cells, and aromatase (ARO) is a crucial Enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

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