Development of chimeric molecules that degrade the estrogen recep-tor using decoy oligonucleotide ligands

Targeted protein degradation using chimeric small molecules, such as proteolysis-targeting chimeras (PROTACs) and specif-ic and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), has attracted attention as a method to degrade 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 the estrogen receptor alpha (ERalpha) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) was found to selectively degrade ERalpha via the UPS. These findings will be applicable to the development of other oligonucleotide-type degraders that target different TFs.