Inhibition of nucleotide excision repair proteins associated with cancer chemotherapy

DNA repair is involved in the cellular response to alkylating agents used for the treatment of various cancers, decreasing the damages induced by the compounds and thus limiting the efficacy of the drugs. The inhibition of DNA repair should therefore increase the cytotoxic effect of alkylating agents, and this has been suggested as a therapeutic approach to increase clinical success. In this review, we focus on proteins involved in Nucleotide Excision Repair (NER) with a particular emphasis on the heterodimer ERCC1/XPF, and give an overview of preclinical and clinical studies underlying this therapeutic approach, as well as details on studies and compounds with notable activities. We also discuss the use of computer-aided methods to develop small molecule inhibitors targeting NER-related proteins, with a focus on structure-based virtual screening, and reflect on future perspectives on this topic. Although interesting results are obtained on cell models with various molecules, we believe new efforts are needed in order to validate the proof of concept in vivo and to translate the use of NER inhibitors in cancer patients.