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Molecular Pharmacology

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Research ArticleArticle

Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis

Jordan J. Toutounchian, Jayaprakash Pagadala, Duane D. Miller, Jerome Baudry, Frank Park, Edward Chaum and Charles R. Yates
Molecular Pharmacology January 2017, 91 (1) 1-13; DOI: https://doi.org/10.1124/mol.116.105031
Jordan J. Toutounchian
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Jayaprakash Pagadala
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Duane D. Miller
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Jerome Baudry
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Frank Park
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Edward Chaum
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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Charles R. Yates
Department of Pharmaceutical Sciences (J.J.T., J.P., D.D.M., F.P., C.R.Y.) and Department of Ophthalmology (E.C., C.R.Y.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Cellular and Molecular Biology at The University of Tennessee, Knoxville, Tennessee; and UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee (J.B.)
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This article has a correction. Please see:

  • Correction to “Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis” - December 01, 2017

Abstract

Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor–induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions using the small molecule JP-153 inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473), resulting in reduced migration and proliferation of retinal endothelial cells stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the focal adhesion protein paxillin is an effective strategy for treating pathologic retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting focal adhesion protein interactions that are essential for pathologic neovascularization in the eye.

Footnotes

    • Received May 9, 2016.
    • Accepted October 28, 2016.
  • This work was funded by the University of Tennessee College of Pharmacy (Pharmaceutical Sciences) Research Enhancement Seed Grant (2014) and the University of Tennessee Research Foundation’s Technology Maturation Fund Program (2015). Conflict of interest statement: Jordan J. Toutounchian, Jayaprakash Pagadala, Duane D. Miller, Frank Park and Charles R. Yates are listed on the patent application entitled “Inhibitors of paxillin binding and related compositions and methods” US Patent Application number 61/935,616. JP-153 is a patent-pending technology owned by the University of Tennessee Research Foundation. No competing financial interests exist for authors Jerome Baudry or Edward Chaum.

  • Portions of this work were previously presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Denver, CO, June 2015, and published as Toutounchian JJ, Pagadala J, Miller DD, Steinle JJ, and Yates R (2015) The role of a Src/FAK-paxillin signalsome in VEGF-induced retinal neovascularization. Invest Ophthalmol Vis Sci 56:208–208.

  • dx.doi.org/10.1124/mol.116.105031.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 91 (1)
Molecular Pharmacology
Vol. 91, Issue 1
1 Jan 2017
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Research ArticleArticle

Targeting Src/FAK/Paxillin Signalsome in Neovascular Disease

Jordan J. Toutounchian, Jayaprakash Pagadala, Duane D. Miller, Jerome Baudry, Frank Park, Edward Chaum and Charles R. Yates
Molecular Pharmacology January 1, 2017, 91 (1) 1-13; DOI: https://doi.org/10.1124/mol.116.105031

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Research ArticleArticle

Targeting Src/FAK/Paxillin Signalsome in Neovascular Disease

Jordan J. Toutounchian, Jayaprakash Pagadala, Duane D. Miller, Jerome Baudry, Frank Park, Edward Chaum and Charles R. Yates
Molecular Pharmacology January 1, 2017, 91 (1) 1-13; DOI: https://doi.org/10.1124/mol.116.105031
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