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Research ArticleArticle

Virtual Screening for LPA2-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

Gyöngyi N. Kiss, James I. Fells, Renuka Gupte, Sue-Chin Lee, Jianxiong Liu, Nóra Nusser, Keng G. Lim, Ramesh M. Ray, Fang-Tsyr Lin, Abby L. Parrill, Balázs Sümegi, Duane D. Miller and Gabor Tigyi
Molecular Pharmacology December 2012, 82 (6) 1162-1173; DOI: https://doi.org/10.1124/mol.112.079699
Gyöngyi N. Kiss
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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James I. Fells
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Renuka Gupte
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Sue-Chin Lee
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Jianxiong Liu
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Nóra Nusser
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Keng G. Lim
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Ramesh M. Ray
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Fang-Tsyr Lin
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Abby L. Parrill
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Balázs Sümegi
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Duane D. Miller
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Gabor Tigyi
Department of Physiology (G.N.K., J.I.F., S.-C.L., J.L., N.N., K.G.L., R.M.R., G.T.) and Department of Pharmaceutical Sciences (R.G., D.M.D.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary (G.N.K., B.S.); Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas (F.-T.L.); and Computational Research on Materials Institute, Department of Chemistry, University of Memphis, Tennessee (A.L.P.)
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Abstract

Lysophosphatidic acid (LPA) is a highly potent endogenous lipid mediator that protects and rescues cells from programmed cell death. Earlier work identified the LPA2 G protein-coupled receptor subtype as an important molecular target of LPA mediating antiapoptotic signaling. Here we describe the results of a virtual screen using single-reference similarity searching that yielded compounds 2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (NSC12404), 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), 4,5-dichloro-2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (H2L5547924), and 2-((9,10-dioxo-9,10-dihydroanthracen-2-yl)carbamoyl) benzoic acid (H2L5828102), novel nonlipid and drug-like compounds that are specific for the LPA2 receptor subtype. We characterized the antiapoptotic action of one of these compounds, GRI977143, which was effective in reducing activation of caspases 3, 7, 8, and 9 and inhibited poly(ADP-ribose)polymerase 1 cleavage and DNA fragmentation in different extrinsic and intrinsic models of apoptosis in vitro. Furthermore, GRI977143 promoted carcinoma cell invasion of human umbilical vein endothelial cell monolayers and fibroblast proliferation. The antiapoptotic cellular signaling responses were present selectively in mouse embryonic fibroblast cells derived from LPA1&2 double-knockout mice reconstituted with the LPA2 receptor and were absent in vector-transduced control cells. GRI977143 was an effective stimulator of extracellular signal-regulated kinase 1/2 activation and promoted the assembly of a macromolecular signaling complex consisting of LPA2, Na+-H+ exchange regulatory factor 2, and thyroid receptor interacting protein 6, which has been shown previously to be a required step in LPA-induced antiapoptotic signaling. The present findings indicate that nonlipid LPA2-specific agonists represent an excellent starting point for development of lead compounds with potential therapeutic utility for preventing the programmed cell death involved in many types of degenerative and inflammatory diseases.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This research was supported by the National Institutes of Health National Institute of Allergy [Medical Countermeasures Radiological and Nuclear Threats Program AI80405].

  • G.T. is a founder of RxBio, Inc.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.079699.

  • ABBREVIATIONS:

    LPA
    lysophosphatidic acid
    S1P
    sphingosine-1-phosphate
    OTP
    octadecenyl thiophosphate
    GPCR
    G protein-coupled receptor
    Ki16425
    3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid
    AM152
    (R)-1-phenylethyl-5-(4-biphenyl-4-cyclopropanecarboxylic acid)-3-methylisoxazole-4-yl carbamate sodium salt
    AM095
    sodium, (4′-(3-methyl-4-((R)-1-phenylethoxycarbonylamino)-isoxazol-5-yl)-biphenyl-4-yl)-acetate
    GRI977143
    2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid
    GRI
    Genome Research Institute
    Bax
    Bcl-2-associated X protein
    PARP-1
    poly(ADP-ribose)polymerase 1
    ERK1/2
    extracellular signal regulated kinases 1/2
    TRIP6
    thyroid receptor interacting protein 6
    NHERF2
    Na+-H+ exchange regulatory factor 2
    NSC12404
    2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid
    H2L
    Hit2Lead
    H2L5547924
    4,5-dichloro-2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid
    H2L5828102
    2-((9,10-dioxo-9,10-dihydroanthracen-2-yl)carbamoyl)benzoic acid
    PBS
    phosphate-buffered saline
    MOE
    Molecular Operating Environment
    UC-DDC
    University of Cincinnati Drug Discovery Center
    TM
    transmembrane
    MEF
    mouse embryonic fibroblast
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    IEC-6
    intestinal epithelial cell line 6
    RH7777
    McArdle rat hepatoma cell line
    LPAR
    LPA receptor
    HUVEC
    human umbilical vein endothelial cell
    TNF-α
    tumor necrosis factor α
    CHX
    cycloheximide
    EGFP
    enhanced green fluorescent protein.

  • Received April 29, 2012.
  • Accepted September 10, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Research ArticleArticle

Nonlipid LPA2-Specific Agonist with Antiapoptotic Action

Gyöngyi N. Kiss, James I. Fells, Renuka Gupte, Sue-Chin Lee, Jianxiong Liu, Nóra Nusser, Keng G. Lim, Ramesh M. Ray, Fang-Tsyr Lin, Abby L. Parrill, Balázs Sümegi, Duane D. Miller and Gabor Tigyi
Molecular Pharmacology December 1, 2012, 82 (6) 1162-1173; DOI: https://doi.org/10.1124/mol.112.079699

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Research ArticleArticle

Nonlipid LPA2-Specific Agonist with Antiapoptotic Action

Gyöngyi N. Kiss, James I. Fells, Renuka Gupte, Sue-Chin Lee, Jianxiong Liu, Nóra Nusser, Keng G. Lim, Ramesh M. Ray, Fang-Tsyr Lin, Abby L. Parrill, Balázs Sümegi, Duane D. Miller and Gabor Tigyi
Molecular Pharmacology December 1, 2012, 82 (6) 1162-1173; DOI: https://doi.org/10.1124/mol.112.079699
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