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

Miyako Naganuma; Nobumichi Ohoka; Genichiro Tsuji; Haruna Tsujimura; Kenji Matsuno; Takao Inoue; Mikihiko Naito; Yosuke Demizu

doi:10.1021/acsmedchemlett.1c00629

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

ACS Med Chem Lett. 2021 Dec 17;13(1):134-139. doi: 10.1021/acsmedchemlett.1c00629. eCollection 2022 Jan 13.

Authors

Miyako Naganuma^{1

2

3}, Nobumichi Ohoka⁴, Genichiro Tsuji¹, Haruna Tsujimura^{1

2}, Kenji Matsuno³, Takao Inoue⁴, Mikihiko Naito⁵, Yosuke Demizu^{1

2}

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
² Graduate School of Medical Life Science, Yokohama City University, Kanagawa 236-0027, Japan.
³ Department of Chemistry and Life Science, Kogakuin University, Tokyo 192-0015, Japan.
⁴ Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 158-8501, Japan.
⁵ Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.

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 LCL-ER(dec), which consists of a decoy oligonucleotide that can bind to estrogen receptor α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) 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.