Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1–XPF

The ERCC1–XPF heterodimer is a 5′–3′ structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1–XPF is primarily involved in the repair of chemically induced helix-distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand cross-links. Inhibition of ERCC1–XPF has been shown to potentiate cytotoxicity of platinum-based drugs and cyclophosphamide in cancer cells. In this study, the previously described ERCC1–XPF inhibitor 4-((6-chloro-2-methoxyacridin-9-yl)­amino)-2-((4-methylpiperazin-1-yl)­methyl)­phenol (compound 1) was used as a reference compound. Following the outcome of docking-based virtual screening (VS), we synthesized seven novel derivatives of 1 that were identified in silico as being likely to have high binding affinity for the ERCC1–XPF heterodimerization interface by interacting with the XPF double helix–hairpin–helix (HhH2) domain. Two of the new compounds, 4-((6-chloro-2-methoxyacridin-9-yl)­amino)-2-((4-cyclohexylpiperazin-1-yl)­methyl)­phenol (compound 3) and 4-((6-chloro-2-methoxyacridin-9-yl)­amino)-2-((4-(2-(dimethylamino)­ethyl) piperazin-1-yl) methyl) phenol (compound 4), were shown to be potent inhibitors of ERCC1–XPF activity in vitro. Compound 4 showed significant inhibition of the removal of CPDs in UV-irradiated cells and the capacity to sensitize colorectal cancer cells to UV radiation and cyclophosphamide.