Degradation of Polo-like Kinase 1 by the Novel Poly-Arginine N‑Degron Pathway PROTAC Regulates Tumor Growth in Nonsmall Cell Lung Cancer

Polo-like
kinase 1 (PLK1), which is crucial in cell cycle
regulation,
is considered a promising anticancer drug target. Herein, we present
the N-degron pathway-based proteolysis targeting chimera (PROTAC)
for PLK1 degradation, targeting the Polo-box domain (PBD). We identified
DD-2 as the most potent PROTAC that selectively induces PLK1 degradation
in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC),
through the N-degron pathway. DD-2 exhibited significant in vitro
anticancer effects, inducing G2/M arrest and apoptosis in HeLa and
NSCLC cell lines. DD-2 showed significant tumor growth inhibition
in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting
its potential in cancer treatment. Furthermore, the combination of
DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively
suppressed tumor growth in double-mutated H1975 cell lines, emphasizing
DD-2’s potential in combination cancer therapies. Collectively,
this study demonstrates the potential of the N-degron pathway, especially
using DD-2, for targeted cancer therapies.