- TARGETING DNA REPAIR IN TUMOR CELLS VIA INHIBITION OF ERCC1-XPF
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The current application relates to pyronaridine or 6-chloro-2-methoxyacridine analogs having binding affinity for the ERCC1-XPF hetero-dimerization interface. The compounds can be used for targeting DNA repair in tumor cells via ERCC1-XPF inhibition, ther
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Paragraph 00234; 00325-00326
(2020/12/30)
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- Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF
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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.
- Elmenoufy, Ahmed H.,Gentile, Francesco,Jay, David,Karimi-Busheri, Feridoun,Yang, Xiaoyan,Soueidan, Olivier M.,Weilbeer, Claudia,Mani, Rajam S.,Barakat, Khaled H.,Tuszynski, Jack A.,Weinfeld, Michael,West, Frederick G.
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p. 7684 - 7696
(2019/10/11)
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