Small-Molecule Inhibitors of Nucleotide Excision Repair
Here we report series of small-molecule inhibitors of interactions between XPA and ERCC1 identified by high-throughput screening (HTS) of compound libraries.
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Background
XPF/ERCC1 is a structure-specific nuclease whose activity is essential for nucleotide excision repair (NER), interstrand crosslink repair (ICL) and other pathways of DNA damage repair. In NER, the recruitment and activation of XPF/ERCC1 depend on the interaction with XPA, another essential component of the NER preincision complex.
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Here we report series of small-molecule inhibitors of interactions between XPA and ERCC1 identified by high-throughput screening (HTS) of compound libraries. 2,3,4,5-tetrahydro-1,5-dioxopyrrolo[1,2-a]quinazoline derivatives bind in the XPA-binding pocket of the ERCC1 central domain and act as competitive inhibitors of XPA-ERCC1 interactions. These compounds inhibit NER in cell extracts and sensitize A549 human lung cancer cells to UV irradiation. Structures of protein-inhibitor complexes determined by X-ray crystallography identify key intermolecular contacts and suggest strategies for compound optimization. We also report preliminary investigations of structure-activity relationships in this compound family. Our studies establish feasibility of NER inhibition by drug-like low-molecular-weight compounds that bind in the XPA-binding pocket of ERCC1.