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

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 alpha (ER alpha) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) was found to selectively degrade ER alpha via the UPS. These findings will be applicable to the development of other oligonucleotide-type degraders that target different TFs.

Automated summary

Targeted protein degradation using chimeric small molecules like PROTACs and SNIPERs has gained attention, but developing degraders without suitable small-molecule ligands for target proteins is challenging. A new chimeric molecule, LCL-ER(dec), selectively degrades ER alpha via a click reaction, showing promise for the development of other oligonucleotide-type degraders targeting various transcription factors.