Small-Molecule Inhibitors of Nucleotide Excision Repair

Respiratory
Oncology

Here we report series of small-molecule inhibitors of interactions between XPA and ERCC1 identified by high-throughput screening (HTS) of compound libraries.

Project Team

Prof. Dmitri Ivanov
Prof. Dmitri Ivanov

Institutions

University of Texas San Antonio
University of Texas San Antonio
US

Project Status

Clinical Stage
Preclinical
Patent Status
Patent not filed

Funding Opportunity

Opportunity type
Funding requested
$0
Funding allocated
$0

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.

Project Details

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.