{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:38:10Z","timestamp":1786977490299,"version":"build-2736575974"},"reference-count":68,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01GM052504"],"award-info":[{"award-number":["5R01GM052504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2024,4,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin\u2010resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin\u2010DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein\u2010protein 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\u2010damaging platinum\u2010based cancer therapy. Here, we report on new small\u2010molecule antagonists of the ERCC1\/XPA protein\u2010protein interaction (PPI) discovered using a high\u2010throughput competitive fluorescence polarization binding assay. We discovered a unique structural class of thiopyridine\u20103\u2010carbonitrile PPI antagonists that block a truncated XPA polypeptide from binding to ERCC1. Preliminary hit\u2010to\u2010lead studies from compound\n                    <jats:bold>1<\/jats:bold>\n                    reveal structure\u2010activity relationships (SAR) and identify lead compound\n                    <jats:bold>27\u2009o<\/jats:bold>\n                    with an EC\n                    <jats:sub>50<\/jats:sub>\n                    of 4.7\u2005\u03bcM. Furthermore, chemical shift perturbation mapping by NMR confirms that\n                    <jats:bold>1<\/jats:bold>\n                    binds within the same site as the truncated XPA\n                    <jats:sub>67\u201380<\/jats:sub>\n                    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\u2010based chemotherapy.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202300648","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T13:48:09Z","timestamp":1706795289000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Small Molecule Antagonists of the DNA Repair ERCC1\/XPA Protein\u2010Protein Interaction"],"prefix":"10.1002","volume":"19","author":[{"given":"Robert","family":"Obermann","sequence":"first","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bereket","family":"Yemane","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassie","family":"Jarvis","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco M.","family":"Franco","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevhenii","family":"Kyriukha","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Nolan","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Gohara","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej M.","family":"Krezel","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Wildman","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. Euclid Ave., Box 8231 St. Louis MO 63110 USA Tel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9888-5411","authenticated-orcid":false,"given":"James W.","family":"Janetka","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine Department of Biochemistry and Molecular Biophysics  660 S. 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