Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor
Haruna Tsujimura, Miyako Naganuma, Nobumichi Ohoka, Takao Inoué, Mikihiko Naito, Genichiro Tsuji, Yosuke Demizu
Abstract
Targeted protein degradation (TPD), using chimeric molecules such as proteolysis-targeting chimeras (PROTACs), has attracted attention as a strategy for selective degradation of intracellular proteins by hijacking the ubiquitin-proteasome system (UPS). However, it is often difficult to develop such degraders due to the absence of appropriate ligands for target proteins. In targeting proteins for degradation, the application of nucleic acid aptamers is considered to be effective because these can be explored using systematic evolution of ligand by exponential enrichment (SELEX) methods. In this study, we constructed chimeric molecules in which nucleic acid aptamers capable of binding to the estrogen receptor α (ERα) and E3 ubiquitin ligase ligands were linked via a linker. ERα aptamer-based PROTACs were found to degrade ERα via the UPS. These findings represent the development of novel aptamer-based PROTACs that target intracellular proteins and are potentially applicable to other proteins.