Development of Chimeric Molecules That Degrade the Estrogen Receptor Using Decoy Oligonucleotide Ligands

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Jan 21

PMID 35059133

Authors

Miyako Naganuma

Nobumichi Ohoka

Genichiro Tsuji

Haruna Tsujimura

Kenji Matsuno

Takao Inoue

Mikihiko Naito

Yosuke Demizu

Affiliations

Soon will be listed here.

Abstract

Targeted protein degradation using chimeric small molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), has attracted attention as a method for degrading intracellular target proteins via the ubiquitin-proteasome system (UPS). These chimeric molecules target a variety of proteins using small molecules that can bind to the proteins. However, it is difficult to develop such degraders in the absence of suitable small-molecule ligands for the target proteins, such as for transcription factors (TFs). Therefore, we constructed the chimeric molecule , which consists of a decoy oligonucleotide that can bind to estrogen receptor α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction. was found to selectively degrade ERα via the UPS. These findings will be applicable to the development of other oligonucleotide-type degraders that target different TFs.

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