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.
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Authors | Xinyan Zhang, Zhilin Zhang, Xiaoqi Xue, Tingting Fan, Chunyan Tan, Feng Liu, Ying Tan, Yuyang Jiang |
Journal | ACS pharmacology & translational science
(ACS Pharmacol Transl Sci)
Vol. 5
Issue 11
Pg. 1109-1118
(Nov 11 2022)
ISSN: 2575-9108 [Electronic] United States |
PMID | 36407946
(Publication Type: Journal Article)
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Copyright | © 2022 American Chemical Society. |