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

Xinyan Zhang; Zhilin Zhang; Xiaoqi Xue; Tingting Fan; Chunyan Tan; Feng Liu; Ying Tan; Yuyang Jiang

doi:10.1021/acsptsci.2c00109

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

ACS Pharmacol Transl Sci. 2022 Oct 12;5(11):1109-1118. doi: 10.1021/acsptsci.2c00109. eCollection 2022 Nov 11.

Authors

Xinyan Zhang¹, Zhilin Zhang¹, Xiaoqi Xue¹, Tingting Fan¹, Chunyan Tan¹, Feng Liu¹, Ying Tan¹, Yuyang Jiang¹

Affiliation

¹ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School Tsinghua University, Shenzhen 518055, China.

Abstract

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.