1. Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF.
- Author
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Elmenoufy AH, Gentile F, Jay D, Karimi-Busheri F, Yang X, Soueidan OM, Weilbeer C, Mani RS, Barakat KH, Tuszynski JA, Weinfeld M, and West FG
- Subjects
- DNA-Binding Proteins metabolism, Dose-Response Relationship, Drug, Drug Design, Endonucleases metabolism, HCT116 Cells, Humans, Models, Molecular, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, DNA Repair, DNA, Neoplasm drug effects, DNA-Binding Proteins antagonists & inhibitors, Endonucleases antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
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.
- Published
- 2019
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