Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein-Protein Interaction
© 2024 Wiley‐VCH GmbH..
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 EC50 of 4.7 μM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA67-80 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
ChemMedChem - 19(2024), 8 vom: 16. Apr., Seite e202300648 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Obermann, Robert [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cmdc.202300648 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 EC50 of 4.7 μM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA67-80 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DNA damage and repair, cisplatin, chemotherapy | |
| 650 | 4 | |a ERCC1, XPA, XPF | |
| 650 | 4 | |a NMR structure | |
| 650 | 4 | |a high-throughput screening (HTS) | |
| 650 | 4 | |a nucleotide excision repair (NER) | |
| 650 | 4 | |a protein-protein interaction (PPI) | |
| 650 | 4 | |a small molecule inhibitor | |
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| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a XPA protein, human |2 NLM | |
| 700 | 1 | |a Yemane, Bereket |e verfasserin |4 aut | |
| 700 | 1 | |a Jarvis, Cassie |e verfasserin |4 aut | |
| 700 | 1 | |a Franco, Francisco M |e verfasserin |4 aut | |
| 700 | 1 | |a Kyriukha, Yevhenii |e verfasserin |4 aut | |
| 700 | 1 | |a Nolan, William |e verfasserin |4 aut | |
| 700 | 1 | |a Gohara, Beth |e verfasserin |4 aut | |
| 700 | 1 | |a Krezel, Andrzej M |e verfasserin |4 aut | |
| 700 | 1 | |a Wildman, Scott A |e verfasserin |4 aut | |
| 700 | 1 | |a Janetka, James W |e verfasserin |4 aut | |
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