American Chemical Society
jm3c01493_si_001.pdf (1.01 MB)

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

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journal contribution
posted on 2023-12-18, 07:20 authored by Pethaiah Gunasekaran, Yeon Sil Hwang, Gong-Hyeon Lee, Jaehui Park, Jung Gi Kim, Yeo Kyung La, Nam Yeong Park, Rajesh Kothandaraman, Min Su Yim, Joonhyeok Choi, Hak Nam Kim, Il Yeong Park, Soo Jae Lee, Mi-Hyun Kim, Hyunjoo Cha-Molstad, Song Yub Shin, Eun Kyoung Ryu, Jeong Kyu Bang
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.