Computational Design of a Non‐lipid LPA2 Receptor Agonist With Antiapoptotic and Radioprotective Action

Lysophosphatidic acid (LPA) is a growth factor‐like lysophospholipis that rescues apoptotically condemned cells. LPA protects IEC‐6 intestinal epithelial cells in vitro and intestinal crypts in vivo from radiation‐induced apoptosis. Using LPA receptor KO mice we established that the LPA2 receptor subtype plays an essential role in the antiapoptotic mechanism. Through its C‐terminal PDZ and LIM‐binding motifs LPA2 forms agonist‐dependent macromolecular signaling complexes. LPA2 interacts with the proapoptotic protein Siva‐1 and targets it for proteasomal degradation, which in turn arrests DNA‐damage‐activated apoptosis. Full activation of the NFkB and ERK1/2 prosurvival pathway requires formation of an LPA2, NHERF2, and TRIP‐6 ternary macromolecular complex. These signals inhibit the intrinsic mitochondrial apoptosis pathway. Furthermore, transfection of the LPA2 receptor into mouse embryonic fibroblasts derived from LPA1/2 double knockout mice restores LPA‐dependent radioprotection. Conditioned medium from gamma‐irradiated U937 cells induces bystander apoptosis in non‐irradiated IEC‐6 cultures and LPA2‐transfected MEFs. Using a validated computational model of the LPA2 receptor we developed a pharmacophore model and used it for in silico drug discovery of non‐lipid LPA2 agonists. We found a novel LPA2‐selective agonist GRI977143, which elicits an antiapoptotic effect and protects IEC‐6 cells from radiation‐ and chemotherapy‐induced apoptosis. GRI977143 also increases the survival of mice exposed to lethal levels of radiation. Supported by CA92160 and AI08405.