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

Journal of Medicinal Chemistry
Ahmed H ElmenoufyFrederick G West

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 ERCC...Continue Reading

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Citations

Oct 4, 2019·Journal of Computer-aided Molecular Design·Jordane Preto, Francesco Gentile
Jan 1, 2020·Chemical Biology & Drug Design·Francesco GentileJack A Tuszynski
Jan 6, 2021·Cancer Chemotherapy and Pharmacology·Gloria CinieroLars Petter Jordheim
Dec 10, 2020·International Journal of Molecular Sciences·Mingrui DuanPeng Mao
Jun 8, 2021·Frontiers in Pharmacology·Jieyu ZhangZhengmin Li
Aug 31, 2021·RSC Chemical Biology·Kerry Silva McPherson, Dmitry M Korzhnev

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