Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions

Gyöngyi N. Kiss, James I. Fells, Renuka Gupte, Sue Lee, Jianxiong Liu, Nóra Nusser, Keng G. Lim, Ramesh M. Ray, Fang Tsyr Lin, Abby L. Parrill, Balázs Sümegi, Duane Miller, Gabor Tigyi

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 (H2L55-47924), 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&2double-knockout mice reconstituted with the LPA 2 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.

Original languageEnglish (US)
Pages (from-to)1162-1173
Number of pages12
JournalMolecular Pharmacology
Volume82
Issue number6
DOIs
StatePublished - Dec 1 2012

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Benzoic Acid
Lysophosphatidic Acid Receptors
Mediator Complex Subunit 1
Cell Death
Fibroblasts
Macromolecular Substances
Caspase 7
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Human Umbilical Vein Endothelial Cells
DNA Fragmentation
G-Protein-Coupled Receptors
Knockout Mice
Caspase 3
Apoptosis
Carcinoma
Lipids
Pharmaceutical Preparations
lysophosphatidic acid
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

Cite this

Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions. / Kiss, Gyöngyi N.; Fells, James I.; Gupte, Renuka; Lee, Sue; Liu, Jianxiong; Nusser, Nóra; Lim, Keng G.; Ray, Ramesh M.; Lin, Fang Tsyr; Parrill, Abby L.; Sümegi, Balázs; Miller, Duane; Tigyi, Gabor.

In: Molecular Pharmacology, Vol. 82, No. 6, 01.12.2012, p. 1162-1173.

Research output: Contribution to journalArticle

Kiss, GN, Fells, JI, Gupte, R, Lee, S, Liu, J, Nusser, N, Lim, KG, Ray, RM, Lin, FT, Parrill, AL, Sümegi, B, Miller, D & Tigyi, G 2012, 'Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions', Molecular Pharmacology, vol. 82, no. 6, pp. 1162-1173. https://doi.org/10.1124/mol.112.079699
Kiss, Gyöngyi N. ; Fells, James I. ; Gupte, Renuka ; Lee, Sue ; Liu, Jianxiong ; Nusser, Nóra ; Lim, Keng G. ; Ray, Ramesh M. ; Lin, Fang Tsyr ; Parrill, Abby L. ; Sümegi, Balázs ; Miller, Duane ; Tigyi, Gabor. / Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions. In: Molecular Pharmacology. 2012 ; Vol. 82, No. 6. pp. 1162-1173.
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