PT  - JOURNAL ARTICLE
AU  - Gyongyi N. Kiss
AU  - James I. Fells
AU  - Renuka Gupte
AU  - Sue-Chin Lee
AU  - Jianxiong Liu
AU  - Nora Nusser
AU  - Keng Gatt Lim
AU  - Ramesh M. Ray
AU  - Fang-Tsyr Lin
AU  - Abby L. Parrill
AU  - Balazs Sumegi
AU  - Duane D. Miller
AU  - Gabor J. Tigyi
TI  - Virtual Screening for LPA2-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions
AID  - 10.1124/mol.112.079699
DP  - 2012 Jan 01
TA  - Molecular Pharmacology
PG  - mol.112.079699
4099  - http://molpharm.aspetjournals.org/content/early/2012/09/11/mol.112.079699.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/09/11/mol.112.079699.full
AB  - 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 the antiapoptotic signaling. Here we describe the results of a virtual screen using single-reference similarity searching that yielded compounds NSC12404, GRI977143, H2L5547924, and H2L5828102, novel nonlipid and drug-like hits that are specific for the LPA2 receptor subtype. We characterized the antiapoptotic action of one of these hits GRI977143 that 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. These 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 kinases 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 as 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.