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Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

Sardar Pasha Sheik Pran Babu, View ORCID ProfileKamakshi Sishtla, Rania S. Sulaiman, View ORCID ProfileBomina Park, Trupti Shetty, Fenil Shah, View ORCID ProfileMelissa L. Fishel, James H. Wikel, View ORCID ProfileMark R. Kelley, Timothy W. Corson
doi: https://doi.org/10.1101/296590
Sardar Pasha Sheik Pran Babu
Indiana University School of Medicine;
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Kamakshi Sishtla
Indiana University School of Medicine;
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Rania S. Sulaiman
Indiana University School of Medicine;
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Bomina Park
Indiana University School of Medicine;
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Trupti Shetty
Indiana University School of Medicine;
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Fenil Shah
Indiana University School of Medicine;
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Melissa L. Fishel
Indiana University School of Medicine;
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James H. Wikel
Apexian Pharmaceuticals
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Mark R. Kelley
Indiana University School of Medicine;
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Timothy W. Corson
Indiana University School of Medicine;
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  • For correspondence: tcorson@iu.edu
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Abstract

Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-κB and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1's function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 μM, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a; GI50 APX2009: 26 μM, APX2014: 5.0 μM). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-κB activation and downstream targets. Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p < 0.0001, ANOVA with Dunnett's post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for CNV in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

Footnotes

  • New Figs. 3 and 6 added with corresponding Methods and Results text; new authors added; supplemental files updated (new Supplemental Figs 1-3).

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 23, 2018.
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Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization
Sardar Pasha Sheik Pran Babu, Kamakshi Sishtla, Rania S. Sulaiman, Bomina Park, Trupti Shetty, Fenil Shah, Melissa L. Fishel, James H. Wikel, Mark R. Kelley, Timothy W. Corson
bioRxiv 296590; doi: https://doi.org/10.1101/296590
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Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization
Sardar Pasha Sheik Pran Babu, Kamakshi Sishtla, Rania S. Sulaiman, Bomina Park, Trupti Shetty, Fenil Shah, Melissa L. Fishel, James H. Wikel, Mark R. Kelley, Timothy W. Corson
bioRxiv 296590; doi: https://doi.org/10.1101/296590

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