Discovery and Characterization of Small Molecule Inhibitors Targeting Exonuclease 1 for Homologous Recombination-Deficient Cancer Therapy.

ABSTRACT: Human exonuclease 1 (EXO1), a member of the structure-specific nuclease family, plays a critical role in maintaining genome stability by processing DNA double-strand breaks (DSBs), nicks, and replication intermediates during DNA replication and repair. As its exonuclease activity is essential for homologous recombination (HR) and replication fork processing, EXO1 has emerged as a compelling therapeutic target, especially in cancers marked by heightened DNA damage and replication stress. Through high-throughput screening of 45,000 compounds, we identified seven distinct chemical scaffolds that demonstrated effective and selective inhibition of EXO1. Representative compounds from two of the most potent scaffolds, C200 and F684, underwent a comprehensive docking analysis and subsequent site-d

SUBMITTER: Wang Y 

PROVIDER: S-EPMC12186255 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature