Evaluation of protein degradation by new proteolysis targeting chimera in human cervical adenocarcinoma epithelial cells and an in vivo mouse model

Abstract Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic strategy for the treatment and diagnosis of diseases by targeting protein degradation. PROTACs consist of a ligand for the target protein and a recognition motif for E3 ubiquitin ligase via a linker. Polo-like kinase 1 (PLK1) is an important biomarker in cancer cells and is overexpressed in several tumor types. Therefore, we aimed to develop a novel PROTAC targeting PLK1 for degradation using a new recognition motif for E3 ubiquitin ligase, using the N-end rule. In this study, PROTAC DD-1, targeting the PLK1 polo-box domain, was designed using the PLHSpT peptide from a known PLK1 inhibitor. The PROTAC induced ubiquitination through a polyarginine peptide, and the underlying mechanism was evaluated by analyzing protein degradation using western blotting. Moreover, DD-1 inhibits tumor cell proliferation by inducing apoptosis. The in vitro antitumor effects of DD-1 in a human cervical adenocarcinoma epithelial cell line and an in vivo mouse model suggest that it is a promising anticancer agent. Our findings provide new insights into the design of novel PROTACs for targeting PLK1 degradation in cancer therapy.