PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer

作者：Xinyan Zhang, Zhilin Zhang, Xiaoqi Xue, Tingting Fan, Chunyan Tan, Feng Liu, Ying Tan, Yuyang Jiang · 发表于：ACS Pharmacology & Translational Science · 年份：2022 · DOI：10.1021/acsptsci.2c00109 · 被引用次数：36 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Peptidase Inhibition and Analysis

PROteolysis-TArgeting Chimeras (PROTACs) are a powerful class of drugs that selectively degrade the proteins of interest (POIs) through cellular ubiquitination mechanisms. Estrogen receptor α (ERα) plays a vital role in the pathogenesis and treatment of breast cancer. In this work, the DNA-binding domain (DBD) of ERα was selected as the target to avoid drug resistance caused by the ligand-binding domain (LBD) of ERα. The estrogen response element (ERE), a natural DNA sequence binding with DBD of ERα, was chosen as a recognized unit of PROTAC. Therefore, we designed a nucleic acid-conjugated PROTAC, ERE-PROTAC, via a click reaction, in which the ERE sequence recruits ERα and the typical small molecule VH032 recruits the von Hippel-Lindau (VHL) E3 ligase. The proposed ERE-PROTAC showed to efficiently and reversibly degrade ERα in different breast cancer cells by targeting the DBD, indicating its potential to overcome the current resistance caused by LBD mutations.