ArticlePharmacological research2024
New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types.
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Article in Pharmacological research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 22 citations in OpenAlex.
- APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation.Expert opinion on therapeutic targets · 2026Review
- Targeting APE1-Redox Function Reverses SOX9-mediated Chemoresistance in Esophageal Adenocarcinoma.Gastroenterology · 2026Article
- Targeting the APE1 hub: integrating DNA repair and redox signaling for precision management of inflammation-associated diseases.Molecular biology reports · 2026Review
- Targeting APE1 endonuclease activity impairs metastasis and enhances genotoxic therapy response in pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Depletion of Fibrinogen Suppresses Growth of Primary Tumors and Metastasis of Pancreatic Ductal Adenocarcinoma.Gastroenterology · 2026Article
- APX3330 reverses the immunosuppressive tumor microenvironment during colorectal carcinogenesis.Cancer cell international · 2026Article
- A phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: first clinical agent targeting APE1/Ref-1 in cancer.The oncologist · 2026Article
- Targeting APE1 endonuclease activity impairs metastasis and enhances genotoxic therapy response in pancreatic cancer.Research square · 2025Article
- Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-TreatedBiomolecules · 2025Article
- Ref-1 redox activity modulates canonical Wnt signaling in endothelial cells.Redox biology · 2025Article
- DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- L-741626 inhibits hepatocellular carcinoma progression by targeting Ref-1 to suppress MAPK/ERK signalling pathway activity.Biology direct · 2025Article
- Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation.Molecular diversity · 2025Article
- 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
- Targeting APE1/Ref-1 to alleviate formalin-induced pain and spinal neuro-inflammation in rats: a promising therapeutic approach.Frontiers in neuroscience · 2025Article
- [Analysis of clinical features, treatment methods, and prognostic influence factors in patients with malignant peripheral nerve sheath tumor].Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery · 2024Article
- Fast-relaxing hydrogels with reversibly tunable mechanics for dynamic cancer cell culture.Biomaterials advances · 2024Article
- Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research.Journal of cellular signaling · 2024Article
- AP endonuclease 1: Biological updates and advances in activity analysis.Methods in enzymology · 2024Article
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Authors and funding
23 authors at 5 institutions in 1 country.
Silpa GampalaDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Hye-Ran MoonSchool of Mechanical Engineering, Purdue University, West Lafayette, IN 47906, USA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA.
Randall WiremanDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jacqueline PeilDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sonia KiranDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Dana K MitchellDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kylee BrewsterDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Henry MangDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Andi MastersIndiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Clinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Christine BachIndiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Clinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Whitney Smith-KinnamenCenter for Proteome Analysis, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Emma H DoudDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Ratan RaiDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Amber L MosleyDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sara K QuinneyIndiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
D Wade ClappDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Chafiq HamdouchiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
James WikelApexian Pharmaceuticals, Indianapolis, IN, USA.
Chi ZhangIndiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biohealth Informatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Bumsoo HanSchool of Mechanical Engineering, Purdue University, West Lafayette, IN 47906, USA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA.
Millie M GeorgiadisDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Mark R KelleyDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Melissa L FishelDepartment of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: mkelley@iu.edu.
Indiana University – Purdue University Indianapolis · USIndiana University School of MedicinePurdue University West Lafayette · USApeX Therapeutics (United States) · USIndiana University Health · US
Funding
Tumor Microenvironment and Metastasis ProgramP30CA082709 · NCI · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI David W Clapp · 1999 to 2026
$59.3MQuality Assurance and Quality Control Project Management: Improving Submissions and Study Conduct in the Human Subjects Research Prior Approval ProcessUL1TR002529 · NCATS · INDIANA UNIVERSITY INDIANAPOLIS · PI MOE, SHARON M, WIEHE, SARAH ELIZABETH · 2018 to 2022
$27.2MNovel Role of Ref-1 in Pancreatic Cancer Etiology and ProgressionR01CA167291 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI FISHEL, MELISSA L., KELLEY, MARK R. · 2013 to 2022
$5.2MReprogramming PDAC Stroma by Targeting Coagulation in the Tumor MicroenvironmentU01CA274304 · NCI · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · PI Melissa L. Fishel, Matthew J. Flick · 2022 to 2026
$4.6MTargeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated ThrombosisU01HL143403 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI FISHEL, MELISSA L., FLICK, MATTHEW J. · 2018 to 2022
$4.2M(PQ9)Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathyR01CA205166 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI FEHRENBACHER, JILL C, KELLEY, MARK R. · 2017 to 2021
$2.7MHyperglycemia mediated myeloproliferative diseaseR01HL140961 · NHLBI · INDIANA UNIVERSITY INDIANAPOLIS · PI KAPUR, REUBEN · 2019 to 2022
$2.3M(PQ12) Enhancement of DNA repair in neurons via a targeted APE1 small molecule modifier to decrease and reverse chemotherapy-induced peripheral neuropathy (CIPN)R01CA231267 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI FEHRENBACHER, JILL C, KELLEY, MARK R. · 2018 to 2022
$2.3MInvestigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitorsR01CA254110 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI FISHEL, MELISSA L., HAN, BUMSOO · 2021 to 2025
$2.1MMetabolic flux analysis and PDX models to understand therapeutic vulnerabilities following inhibition of Ref-1 redox signaling in pancreatic cancerR01CA282478 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI Melissa L. Fishel, Mark R. Kelley · 2023 to 2026
$2.1MA Fragment-Based Strategy for K-RAS Covalent InhibitorsR01CA264471 · NCI · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · PI MEROUEH, SAMY · 2021 to 2024
$1.9MTargeting the Ref-1 signaling node for treating ocular neovascularizationR01EY031939 · NEI · INDIANA UNIVERSITY INDIANAPOLIS · PI CORSON, TIMOTHY W, KELLEY, MARK R. · 2020 to 2023
$1.7MNCATS NIH HHS UL1 TR002529NCI NIH HHS P30 CA082709NCI NIH HHS R01 CA167291NCI NIH HHS R01 CA205166NCI NIH HHS R01 CA231267NCI NIH HHS R01 CA254110NCI NIH HHS R01 CA264471NCI NIH HHS R01 CA282478NCI NIH HHS U01 CA274304NEI NIH HHS R01 EY031939NHLBI NIH HHS R01 HL140961NHLBI NIH HHS U01 HL143403
Abstract
AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein that is overexpressed in most aggressive cancers and impacts various cancer cell signaling pathways. Ref-1's redox activity plays a significant role in activating transcription factors (TFs) such as NFκB, HIF1α, STAT3 and AP-1, which are crucial contributors to the development of tumors and metastatic growth. Therefore, development of potent, selective inhibitors to target Ref-1 redox function is an appealing approach for therapeutic intervention. A first-generation compound, APX3330 successfully completed phase I clinical trial in adults with progressing solid tumors with favorable response rate, pharmacokinetics (PK), and minimal toxicity. These positive results prompted us to develop more potent analogs of APX3330 to effectively target Ref-1 in solid tumors. In this study, we present structure-activity relationship (SAR) identification and validation of lead compounds that exhibit a greater potency and a similar or better safety profile to APX3330. In order to triage and characterize the most potent and on-target second-generation Ref-1 redox inhibitors, we assayed for PK, mouse and human S9 fraction metabolic stability, in silico ADMET properties, ligand-based WaterLOGSY NMR measurements, pharmacodynamic markers, cell viability in multiple cancer cell types, and two distinct 3-dimensional (3D) cell killing assays (Tumor-Microenvironment on a Chip and 3D spheroid). To characterize the effects of Ref-1 inhibition in vivo, global proteomics was used following treatment with the top four analogs. This study identified and characterized more potent inhibitors of Ref-1 redox function (that outperformed APX3330 by 5-10-fold) with PK studies demonstrating efficacious doses for translation to clinic.
Indexed as
DNA-(Apurinic or Apyrimidinic Site) LyaseNeoplasmsAdultAngiogenesis InhibitorsAnimalsApoptosisBiological AssayHumansMiceTumor MicroenvironmentAngiogenesis InhibitorsDNA-(Apurinic or Apyrimidinic Site) LyaseCancersHypoxia Inducible Factor 1 (HIF1α)MPNSTNovel targeted inhibitorsNuclear Factor kappa B (NFκB)PDACPotencyRef-1 redox function
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