2. Academic Validation
  3. N-Degron-Based PROTAC Targeting PLK1: A Potential Therapeutic Strategy for Cervical Cancer

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

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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