ArticleBiochemistry2013
Inhibition of apurinic/apyrimidinic endonuclease I's redox activity revisited.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 59 citations in OpenAlex.
- Acidic bile salts induce APE1-dependent PRDX2 activation to drive oxaliplatin resistance via ferroptosis inhibition.Redox biology · 2026Article
- APE1/Ref-1 inhibition via APX3330 lowers monocyte/macrophage infiltration without ameliorating the structure and function of dystrophic mdx hindlimb muscles.Physiological reports · 2025Article
- Chemically induced partial unfolding of the multifunctional apurinic/apyrimidinic endonuclease 1.Protein science : a publication of the Protein Society · 2025Review
- Ref-1 redox activity regulates retinal neovascularization by modulating transcriptional activation of HIF-1α.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Ref-1 is overexpressed in neovascular eye disease and targetable with a novel inhibitor.Angiogenesis · 2025Article
- New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types.Pharmacological research · 2024Article
- Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.International journal of molecular sciences · 2023Review
- Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease.The Journal of pharmacology and experimental therapeutics · 2023Review
- Cysteine Oxidation to Sulfenic Acid in APE1 Aids G-Quadruplex Binding While Compromising DNA Repair.ACS chemical biology · 2022Article
- APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b.Cellular and molecular life sciences : CMLS · 2022Article
- RelA Is an Essential Target for Enhancing Cellular Responses to the DNA Repair/Ref-1 Redox Signaling Protein and Restoring Perturbated Cellular Redox Homeostasis in Mouse PDAC Cells.Frontiers in oncology · 2022Article
- APE1/Ref-1 Role in Inflammation and Immune Response.Frontiers in immunology · 2022Review
- Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy.International journal of molecular sciences · 2021Review
- APE1/Ref-1 as a Novel Target for Retinal Diseases.Journal of cellular signaling · 2021Article
- Chemical Inhibition of Apurinic-Apyrimidinic Endonuclease 1 Redox and DNA Repair Functions Affects the Inflammatory Response via Different but Overlapping Mechanisms.Frontiers in cell and developmental biology · 2021Article
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway.DNA repair · 2019Article
- Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination.The Journal of biological chemistry · 2019Article
- The endonuclease APE1 processes miR-92b formation, thereby regulating expression of the tumor suppressor LDLR in cervical cancer cells.Therapeutic advances in medical oncology · 2019Article
- Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization.The Journal of pharmacology and experimental therapeutics · 2018Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
The essential base excision repair protein, apurinic/apyrimidinic endonuclease 1 (APE1), plays an important role in redox regulation in cells and is currently targeted for the development of cancer therapeutics. One compound that binds APE1 directly is (E)-3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid (E3330). Here, we revisit the mechanism by which this negatively charged compound interacts with APE1 and inhibits its redox activity. At high concentrations (millimolar), E3330 interacts with two regions in the endonuclease active site of APE1, as mapped by hydrogen-deuterium exchange mass spectrometry. However, this interaction lowers the melting temperature of APE1, which is consistent with a loss of structure in APE1, as measured by both differential scanning fluorimetry and circular dichroism. These results are consistent with other findings that E3330 concentrations of >100 μM are required to inhibit APE1's endonuclease activity. To determine the role of E3330's negatively charged carboxylate in redox inhibition, we converted the carboxylate to an amide by synthesizing (E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylene]-N-methoxy-undecanamide (E3330-amide), a novel uncharged derivative. E3330-amide has no effect on the melting temperature of APE1, suggesting that it does not interact with the fully folded protein. However, E3330-amide inhibits APE1's redox activity in in vitro electrophoretic mobility shift redox and cell-based transactivation assays, producing IC(50) values (8.5 and 7 μM) lower than those produced with E3330 (20 and 55 μM, respectively). Thus, E3330's negatively charged carboxylate is not required for redox inhibition. Collectively, our results provide additional support for a mechanism of redox inhibition involving interaction of E3330 or E3330-amide with partially unfolded APE1.
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