Constructing a warhead of PROTAC with aptamer for tumor-selective degradation of nucleolin

Abstract PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, although PROTACs are highly efficient for protein degradation, most PROTACs generated lack cell-type selectivity, resulting in potential off-tissue, on-target toxicity. To address this drawback, we herein developed an aptamer-based PROTAC ZL216 using aptamer AS1411 as a targeting ligand for nucleolin, and it showed both excellent serum stability and water solubility. Based on the differential expression of nucleolin on the cell surface, ZL216 can specifically bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced the degradation of nucleolin in vitro and in vivo, thereby inhibiting the proliferation and migration of breast cancer cells. These studies demonstrated the potential of utilizing aptamers to construct PROTACs to achieve the selective degradation of targeted protein in tumor cells and provided a promising strategy for the development of tumor-selective PROTACs.