2. Academic Validation
  3. Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

  • J Med Chem. 2023 May 25;66(10):6631-6651. doi: 10.1021/acs.jmedchem.2c02032.
Baohua Xie 1,  Zhinang Yin 2,  Zhiye Hu 1,  Junhui Lv 2,  Chuanqian Du 1,  Xiangping Deng 3,  Yuan Huang 1,  Qiuzi Li 3,  Jian Huang 3,  Kaiwei Liang 2,  Hai-Bing Zhou 1 4,  Chune Dong 1 4
Affiliations

Affiliations

  • 1 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4 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: 37161783 DOI: 10.1021/acs.jmedchem.2c02032
Abstract

The Estrogen Receptor (ER) is a well-established target for endocrine therapies of ER-positive breast Cancer (ER+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation. These PROTACs showed significant antiproliferation and ERα degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ERα mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ERα target genes and impaired genome-wide ERα binding. Compound ZD12 exhibited excellent antitumor potency and ERα degradation activity in both tamoxifen-sensitive and -resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z