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Pooled shRNA Screen for Reactivation of MeCP2 on the Inactive X Chromosome
Published on: March 2, 2018
Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction
Khaled H Barakat1, Lars P Jordheim, Rolando Perez-Pineiro
1Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
Background:
Nucleotide excision repair (NER) removes many types of DNA lesions including those induced by UV radiation and platinum-based therapy. Resistance to platinum-based therapy correlates with high expression of ERCC1, a major element of the NER machinery. The interaction between ERCC1 and XPA is essential for a successful NER function. Therefore, one way to regulate NER is by inhibiting the activity of ERCC1 and XPA.
Methodology/Principal Findings:
Here we continued our earlier efforts aimed at the identification and characterization of novel inhibitors of the ERCC1-XPA interaction. We used a refined virtual screening approach combined with a biochemical and biological evaluation of the compounds for their ability to interact with ERCC1 and to sensitize cells to UV radiation. Our findings reveal a new validated ERCC1-XPA inhibitor that significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction.
Conclusions:
NER is a major factor in acquiring resistance to platinum-based therapy. Regulating the NER pathway has the potential of improving the efficacy of platinum treatments. One approach that we followed is to inhibit the essential interaction between the two NER elements, ERCC1 and XPA. Here, we performed virtual screening against the ERCC1-XPA interaction and identified novel inhibitors that block the XPA-ERCC1 binding. The identified inhibitors significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction.
Insights
Researchers identified novel inhibitors targeting the ERCC1-XPA interaction, a key component of nucleotide excision repair (NER). These inhibitors sensitized colon cancer cells to UV radiation, suggesting a way to overcome resistance to platinum-based therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Nucleotide excision repair (NER) removes DNA damage, but high ERCC1 expression confers resistance to platinum therapy.
- The ERCC1-XPA interaction is crucial for NER pathway function.
- Inhibiting ERCC1-XPA interaction is a strategy to overcome therapy resistance.
Purpose of the Study:
- Identify and characterize novel inhibitors of the ERCC1-XPA interaction.
- Evaluate the efficacy of these inhibitors in sensitizing cancer cells to DNA-damaging agents.
Main Methods:
- Refined virtual screening for ERCC1-XPA inhibitors.
- Biochemical and cellular assays to assess compound activity.
- Evaluation of sensitization of colon cancer cells to UV radiation.
Main Results:
- A novel validated inhibitor of the ERCC1-XPA interaction was identified.
- The inhibitor demonstrated significant sensitization of colon cancer cells to UV radiation.
- This indicates a strong inhibition of the ERCC1-XPA binding.
Conclusions:
- NER pathway regulation, specifically ERCC1-XPA interaction inhibition, can improve platinum treatment efficacy.
- Novel ERCC1-XPA inhibitors offer a potential strategy to combat platinum resistance in cancer.
- Targeting the ERCC1-XPA interaction is a promising approach for cancer therapy.
