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.