N-Degron-Based PROTAC Targeting PLK1: A Potential Therapeutic Strategy for Cervical Cancer

  • Pharmaceutics. 2025 Aug 7;17(8):1027. doi: 10.3390/pharmaceutics17081027.
Pethaiah Gunasekaran  1  2 ,  Sang Chul Shin  3 ,  Yeon Sil Hwang  2 ,  Jihyeon Lee  2  4 ,  Yeo Kyung La  2 ,  Min Su Yim  5 ,  Hak Nam Kim  1 ,  Tae Wan Kim  6 ,  Eunjung Yang  7 ,  Soo Jae Lee  4 ,  Jung Min Yoon  8 ,  Eunice EunKyeong Kim  8 ,  Seob Jeon  7 ,  Eun Kyoung Ryu  1 ,  Jeong Kyu Bang  1  2
Affiliations
  • 1. Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Cheongju 28119, Republic of Korea.
  • 2. Dandicure Inc., Ochang, Cheongju 28119, Republic of Korea.
  • 3. Convergent Research Support Division, Technological Convergence Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 4. College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.
  • 5. Korea Disease Control and Prevention Agency, National Institute of Health Center for Emerging Virus Research, Division of Emerging Virus and Vector Research, Cheongju 28159, Republic of Korea.
  • 6. Future Innovation Medical Research Center, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Republic of Korea.
  • 7. Department of Obstetrics and Gynecology, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Republic of Korea.
  • 8. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
PMID: 40871048 DOI: 10.3390/pharmaceutics17081027
Abstract

Background: Cervical Cancer remains a major global health concern, with existing chemotherapy facing limited effectiveness owing to resistance. Polo-like kinase 1 (PLK1) overexpression in cervical Cancer cells is a promising target for developing novel therapies to overcome chemoresistance and improve treatment efficacy. Methods: In this study, we developed a novel PROTAC, NC1, targeting PLK1 PBD via the N-end rule pathway. Results: This PROTAC effectively depleted the PLK1 protein in HeLa cells by inducing protein degradation. The crystal structure of the PBD-NC1 complex identified key PLK1 PBD binding interactions and isothermal titration calorimetry (ITC) confirmed a binding affinity of 6.06 µM between NC1 and PLK1 PBD. NC1 significantly decreased cell viability with an IC50 of 5.23 µM, induced G2/M phase arrest, and triggered Apoptosis in HeLa cells. In vivo, NC1 suppressed tumor growth in a HeLa xenograft mouse model. Conclusions: This research highlights the potential of N-degron-based PROTACs targeting the PLK1 protein in Cancer therapies, highlighting their potential in future cervical Anticancer treatment strategies.

Keywords
N-degron; N-end rule pathway; PLK1; PROTAC; anticancer.
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