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

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

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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