New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types

Sep 21, 2026

AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein overexpressed in most aggressive cancers and affects multiple cancer cell signaling pathways. Ref-1 redox activity supports activation of transcription factors including NFκB, HIF1α, STAT3, and AP-1, which contribute to tumor development and metastatic growth. This manuscript focuses on New Ref-1/APE1 targeted inhibitors and evaluates improved potency for clinical applications across multiple cancer types.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages40

Reading Time1 h 41 min

AccessFree to download

Abstract

Background on APE1/Ref-1 and redox activity

Role of transcription factor activation in cancer

Focus on New Ref-1/APE1 targeted inhibitors

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Pharmacol Res. Author manuscript; available in PMC 2024 March 25. | | --- | --- | Published in final edited form as: Pharmacol Res. 2024 March ; 201: 107092. doi:10.1016/j.phrs.2024.107092 . New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types Silpa Gampalaa,b, Hye-ran Moonc,d, Randall Wiremana, Jacqueline Peila, Sonia Kirana,b, Dana K. Mitchella, Kylee Brewstera, Henry Manga, Andi Mastersb,e, Christine Bachb,e, Whitney Smith-Kinnamenf, h, Emma H. Douda,f, h, Ratan Raih, Amber L. Mosleya,f,g,h, Sara K. Quinneyb, h,m, D. Wade Clappa,b, h,i, Chafiq Hamdouchik, James Wikeln, Chi Zhangb, i,j, Bumsoo Hanc,d, Millie M. Georgiadish, Mark R. Kelleya,b, h,l, Melissa L. Fishela,b, l,* a Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA b Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA cSchool of Mechanical Engineering, Purdue University, West Lafayette, IN 47906, USA d Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA eClinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, IN 46202, USA This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). *Correspondence to: 1044 W Walnut St. R4–321, Indianapolis, IN 46202, [USA. mkelley@iu.edu](USA. mkelley@iu.edu), [mfishel@iu.edu](mfishel@iu.edu) (M.L. Fishel) . Ethics approval and consent to participate All animal studies were conducted under the guidelines of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of Indiana University School of Medicine. CRediT authorship contribution statement Millie M. Georgiadis: Writing – review & editing, Supervision, Conceptualization. Christine Bach: Writing – original draft, Resources, Methodology, Investigation, Formal analysis. Whitney Smith-Kinnamen: Supervision, Methodology, Investigation, Formal analysis. Silpa Gampala: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Conceptualization. Mark R. Kelley: Writing – review & editing, Writing – original draft, Supervision, Resources, Funding acquisition, Conceptualization. Melissa L. Fishel: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Emma H. Doud: Writing – original draft, Validation, Software, Methodology, Investigation, Formal analysis. Ratan Rai: Writing – original draft, Methodology, Investigation, Formal analysis. Hye-ran Moon: Writing – review & editing, Visualization, Methodology, Investigation, Formal analysis. Amber L. Mosley: Supervision. Randall Wireman: Writing – review & editing, Methodology, Investigation, Formal analysis. Sara K. Quinney: Supervision. Jacqueline Peil: Validation. D. Wade Clapp: Supervision. Sonia Kiran: Validation. Chafiq Hamdouchi: Writing – original draft, Validation, Supervision, Methodology, Investigation, Conceptualization. Dana K. Mitchell : Methodology. James Wikel: Supervision, Conceptualization. Kylee Brewster: Investigation. Chi Zhang: Writing – original draft, Validation, Methodology, Investigation, Formal analysis. Henry Mang: Investigation. Bumsoo Han: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Andi Masters: Writing – original draft, Methodology, Investigation, Formal analysis. Declaration of Competing Interest None. Mark R. Kelley has licensed APX3330 through Indiana University Research and Technology Co

FAQs

What is APE1/Ref-1 and why is it important in aggressive cancers?

APE1/Ref-1 is a multifunctional protein overexpressed in most aggressive cancers and influences multiple cancer cell signaling pathways.

Which transcription factors are activated by Ref-1 redox activity?

The document states Ref-1 redox activity activates transcription factors such as NFκB, HIF1α, STAT3, and AP-1.

What is the clinical focus of the New Ref-1/APE1 inhibitors described in the manuscript?

The work targets APE1/Ref-1 with inhibitors designed to demonstrate improved potency for clinical applications across multiple cancer types.

Sep 21, 2026

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