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Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor

Claudia Weilbeer1, David Jay2, James C Donnelly1

  • 1Department of Chemistry, University of Alberta, Edmonton, AB, Canada.

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Summary

Researchers developed a novel inhibitor targeting the ERCC1-XPF DNA repair enzyme. This compound enhances cancer cell sensitivity to chemotherapy and radiation, paving the way for improved cancer treatments.

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DNA repairERCC1-XPF small molecule inhibitorscomputer aided drug design (CADD)ionizing and UV irradiationproximity ligation assay

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • DNA repair enzymes are crucial targets for enhancing chemotherapy efficacy.
  • The ERCC1-XPF heterodimer is a key endonuclease involved in DNA repair.
  • Inhibiting ERCC1-XPF heterodimerization sensitizes cancer cells to DNA damage.

Purpose of the Study:

  • To design and synthesize novel ERCC1-XPF inhibitors.
  • To evaluate the efficacy of these inhibitors in vitro and in cell-based assays.
  • To assess the potential of these inhibitors to sensitize cancer cells to DNA damaging agents.

Main Methods:

  • In silico screening of ERCC1-XPF inhibitor modifications.
  • Synthesis of selected inhibitor candidates using late-stage functionalization.
  • In vitro fluorescence-based endonuclease assays.
  • Cell-based assays for nucleotide excision repair inhibition and heterodimerization disruption.
  • Assessment of cancer cell sensitization to UVC, cyclophosphamide, and ionizing radiation.

Main Results:

  • Compound 6 demonstrated potent inhibition of ERCC1-XPF endonuclease activity in vitro.
  • Compound 6 effectively inhibited nucleotide excision repair and disrupted ERCC1-XPF heterodimerization in cell-based assays.
  • Compound 6 sensitized HCT-116 cancer cells to UVC, cyclophosphamide, and ionizing radiation.

Conclusions:

  • The novel inhibitor, compound 6, effectively targets ERCC1-XPF endonuclease activity.
  • Compound 6 shows promise for sensitizing cancer cells to various DNA damaging chemotherapies and radiation.
  • This research represents a significant advancement towards the synergistic application of DNA repair inhibitors and chemotherapeutic drugs in cancer treatment.