Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting...

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Cancer Research

Background:

• The ERCC1-XPF endonuclease is crucial for DNA repair mechanisms, specifically correcting bulky lesions and helix distortions.
• Inhibiting ERCC1-XPF activity can sensitize cancer cells to DNA-damaging agents like UV radiation and certain chemotherapeutics.
• Previous research identified a hit compound (F06) for ERCC1-XPF inhibition.

Purpose of the Study:

• To perform a structure-activity relationship analysis of ERCC1-XPF inhibitors.
• To design, synthesize, and evaluate novel compounds based on the F06 pharmacophore model.
• To identify improved inhibitors with enhanced potency and efficacy.

Main Methods:

• Rational drug design based on a pharmacophore model.
• Synthesis of three series of novel acridine derivatives.
• In vitro screening for ERCC1-XPF inhibitory activity.
• Assessment of binding affinity and potentiation of cytotoxicity.

Main Results:

• Successfully synthesized and screened novel compounds, identifying B9 as a potent ERCC1-XPF inhibitor (IC50 = 0.49 μM).
• Compound B9 demonstrated a 3-fold improvement in inhibitory activity compared to the reference compound F06.
• B9 exhibited enhanced binding affinity and potentiated the cytotoxic effects of UV radiation and cyclophosphamide in colorectal cancer cells.
• B9 inhibited nucleotide excision repair by blocking the removal of cyclobutane pyrimidine dimers (CPDs).

Conclusions:

• Compound B9 represents a significant advancement in ERCC1-XPF inhibitor development.
• B9 shows potential as a therapeutic agent to enhance the efficacy of existing cancer treatments.
• Further investigation into B9's mechanism and efficacy in preclinical models is warranted.