Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Chemotherapy effectiveness, particularly with alkylating agents, is often limited by DNA repair mechanisms.
• The ERCC1-XPF protein complex is a key component of the nucleotide excision repair pathway, crucial for mitigating DNA damage.

Purpose of the Study:

• To identify novel small molecules that inhibit the ERCC1-XPF protein-protein interaction.
• To evaluate the potential of these inhibitors to enhance the efficacy of DNA-damaging cancer therapies.

Main Methods:

• Virtual screening of chemical libraries (National Cancer Institute diversity set, DrugBank) to identify potential ERCC1-XPF inhibitors.
• Experimental validation of top compounds using cancer cell lines (A549, HCT116).
• Assays to assess drug synergy, cytotoxicity, DNA repair modification (γH2AX staining), and direct protein interaction (Biacore).

Main Results:

• A novel compound, NSC 130813, was identified as an inhibitor of the ERCC1-XPF interaction.
• NSC 130813 demonstrated synergistic effects with cisplatin and mitomycin C, and increased UVC-induced cytotoxicity.
• The compound was shown to disrupt ERCC1-XPF interaction in cells and bind to the XPF interaction domain.

Conclusions:

• Targeting the ERCC1-XPF protein-protein interaction with small molecules is a viable strategy.
• Inhibitors like NSC 130813 can potentially enhance the therapeutic effects of alkylating agents in cancer treatment.