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

  • J Med Chem. 2023 Dec 17. doi: 10.1021/acs.jmedchem.3c01493.
Pethaiah Gunasekaran  1  2 ,  Yeon Sil Hwang  1  2 ,  Gong-Hyeon Lee  2 ,  Jaehui Park  3 ,  Jung Gi Kim  4 ,  Yeo Kyung La  1 ,  Nam Yeong Park  1 ,  Rajesh Kothandaraman  2 ,  Min Su Yim  5 ,  Joonhyeok Choi  1 ,  Hak Nam Kim  1 ,  Il Yeong Park  3 ,  Soo Jae Lee  3 ,  Mi-Hyun Kim  6 ,  Hyunjoo Cha-Molstad  4 ,  Song Yub Shin  7 ,  Eun Kyoung Ryu  1  8 ,  Jeong Kyu Bang  1  2  8
Affiliations
  • 1. Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Chungbuk 28119, Republic of Korea.
  • 2. Dandicure Inc, Ochang, Chungbuk 28119, Republic of Korea.
  • 3. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
  • 4. Nucleic Acid Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
  • 5. Division of Vaccine Development Coordination, Center for Vaccine Research, National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju 28159, Republic of Korea.
  • 6. Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea.
  • 7. Department of Cellular and Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea.
  • 8. Department of Bio-Analytical Science, University of Science & Technology, Daejeon 34113, Republic of Korea.
PMID: 38105611 DOI: 10.1021/acs.jmedchem.3c01493
Abstract

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.

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