Zhang Xinyan, Zhang Zhilin, Xue Xiaoqi, Fan Tingting, Tan Chunyan, Liu Feng, Tan Ying, Jiang Yuyang
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School Tsinghua University, Shenzhen 518055, China.
ACS Pharmacol Transl Sci. 2022 Oct 12;5(11):1109-1118. doi: 10.1021/acsptsci.2c00109. eCollection 2022 Nov 11.
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.
蛋白酶靶向嵌合体（PROTACs）是一类强大的药物，可通过细胞泛素化机制选择性降解目标蛋白（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。在这项工作中，选择ERα的DNA结合结构域（DBD）作为靶点，以避免由ERα的配体结合结构域（LBD）引起的耐药性。雌激素反应元件（ERE）是一种与ERα的DBD结合的天然DNA序列，被选为PROTAC的识别单元。因此，我们通过点击反应设计了一种核酸共轭PROTAC，即ERE-PROTAC，其中ERE序列招募ERα，典型的小分子VH032招募冯·希佩尔-林道（VHL）E3连接酶。所提出的ERE-PROTAC通过靶向DBD显示出在不同乳腺癌细胞中有效且可逆地降解ERα的能力，表明其具有克服当前由LBD突变引起的耐药性的潜力。
