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

Pethaiah Gunasekaran1,2, Sang Chul Shin3, Yeon Sil Hwang2

  • 1Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Cheongju 28119, Republic of Korea.

Pharmaceutics
|August 28, 2025
PubMed

Insights

A novel PROTAC molecule, NC1, effectively degrades Polo-like kinase 1 (PLK1) in cervical cancer cells, showing promise for overcoming chemoresistance and inhibiting tumor growth in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cervical cancer presents a significant global health challenge.
  • Current chemotherapy options are limited by resistance, necessitating novel therapeutic strategies.
  • Polo-like kinase 1 (PLK1) is overexpressed in cervical cancer and represents a potential therapeutic target.

Purpose of the Study:

  • To develop a novel Proteolysis-Targeting Chimera (PROTAC) molecule targeting PLK1.
  • To investigate the efficacy of this PROTAC in degrading PLK1 and its impact on cervical cancer cells.
  • To evaluate the therapeutic potential of the PROTAC in preclinical models.

Main Methods:

  • Development of a novel PROTAC, NC1, designed to target the PLK1 protein via the N-end rule pathway.
  • Assessment of PLK1 protein depletion in HeLa cells.
  • Structural analysis of the PBD-NC1 complex and binding affinity determination using Isothermal Titration Calorimetry (ITC).
  • In vitro evaluation of cell viability, cell cycle arrest, and apoptosis induction.
  • In vivo assessment of tumor growth suppression in a HeLa xenograft mouse model.

Main Results:

  • The PROTAC NC1 successfully induced degradation of PLK1 protein in HeLa cells.
  • Structural studies confirmed key binding interactions between NC1 and PLK1 PBD, with an ITC-determined binding affinity of 6.06 µM.
  • NC1 demonstrated significant anti-cancer effects in vitro, including reduced cell viability (IC50 of 5.23 µM), G2/M phase arrest, and apoptosis induction.
  • In vivo studies showed that NC1 suppressed tumor growth in a mouse model.

Conclusions:

  • N-degron-based PROTACs targeting PLK1 are a promising strategy for cancer therapy.
  • The developed PROTAC, NC1, shows significant potential for overcoming chemoresistance in cervical cancer.
  • This research supports the development of novel PLK1-targeting PROTACs for future cervical cancer treatment strategies.
Keywords:
N-degronN-end rule pathwayPLK1PROTACanticancer

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