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PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2022-10-12 , DOI: 10.1021/acsptsci.2c00109
Xinyan Zhang 1 , Zhilin Zhang 1 , Xiaoqi Xue 1 , Tingting Fan 1 , Chunyan Tan 1 , Feng Liu 1 , Ying Tan 1 , Yuyang Jiang 1
Affiliation  

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.

中文翻译:

PROTAC 靶向乳腺癌 DNA 结合域的雌激素受体 α 降解剂

蛋白水解靶向嵌合体 (PROTAC) 是一类功能强大的药物,可通过细胞泛素化机制选择性降解目的蛋白 (POIs)。雌激素受体α(ERα)在乳腺癌的发病机制和治疗中起着至关重要的作用。本工作选择ERα的DNA结合域(DBD)作为靶点,以避免ERα的配体结合域(LBD)引起的耐药性。雌激素反应元件(ERE)是与ERα的DBD结合的天然DNA序列,被选为PROTAC的公认单元。因此,我们通过点击反应设计了一种核酸缀合的PROTAC,ERE-PROTAC,其中ERE序列招募ERα,典型的小分子VH032招募von Hippel-Lindau (VHL) E3连接酶。所提出的 ERE-PROTAC 通过靶向 DBD 来有效且可逆地降解不同乳腺癌细胞中的 ERα,表明其有可能克服目前由 LBD 突变引起的耐药性。
更新日期:2022-10-12
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