Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein‐Protein Interaction

Abstract The DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin‐resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin‐DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein‐protein binding interactions of ERCC1, the endonuclease, XPF, and XPA. Thus, inhibition of their function is a potential therapeutic strategy for the selective sensitization of tumors to DNA‐damaging platinum‐based cancer therapy. Here, we report on new small‐molecule antagonists of the ERCC1/XPA protein‐protein interaction (PPI) discovered using a high‐throughput competitive fluorescence polarization binding assay. We discovered a unique structural class of thiopyridine‐3‐carbonitrile PPI antagonists that block a truncated XPA polypeptide from binding to ERCC1. Preliminary hit‐to‐lead studies from compound 1 reveal structure‐activity relationships (SAR) and identify lead compound 27 o with an EC 50 of 4.7 μM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA 67–80 peptide. These novel ERCC1 antagonists are useful chemical biology tools for investigating DNA damage repair pathways and provide a good starting point for medicinal chemistry optimization as therapeutics for sensitizing tumors to DNA damaging agents and overcoming resistance to platinum‐based chemotherapy.