Inhibition of the ERCC1-XPF structure-specific endonuclease to overcome cancer chemoresistance.

•ERCC1–XPF active site and interaction inhibitors were identified.•ERCC1–XPF heterodimer levels in ovarian cancer cells were reduced.•Active site inhibitors showed specificity for ERCC1–XPF over other nucleases.•Inhibitors blocked NER and enhanced melanoma cell sensitivity to cisplatin.•ERCC1–XPF inhibition could enhance the effectiveness of platinum chemotherapy.