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

Autor: Obermann R; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Yemane B; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Jarvis C; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Franco FM; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Kyriukha Y; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Nolan W; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Gohara B; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Krezel AM; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Wildman SA; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel., Janetka JW; Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., Box 8231, St. Louis, MO, 63110, USA Tel.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Apr 16; Vol. 19 (8), pp. e202300648. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1002/cmdc.202300648
Abstrakt: 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.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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