Specific nonlipid agonists of the lysophosphatidic acid type 2 GPCR with subnanomolar potency mitigate radiation injury (998.2)

Previous studies have identified ligands of the LPA2 GPCR as mitigators of high‐dose radiation injury in vitro and in vivo. These early hit compounds originating from the hit scaffold GRI977143 had EC50 values in the hundred nanomolar range. Lead optimization guided by a validated computational model of the LPA2 GPCR led us to explore the structure‐activity relationship of a group of aromatic sulfonamides. The apparent EC50 value for oleoyl lysophosphatidic acid (LPA 18:1) at LPA2 is 1.4 nM. Synthetic modifications of the aromatic sulfonamide scaffold led to the synthesis of compounds RP 10‐73 and 10‐83, which have subnanomolar potency at LPA2. The EC50 value of ligand activated Ca2+ transient in LPA2 reconstituted mouse embryonic fibroblasts derived from LPA1&2 double knockout mice was 0.15 ± 0.02 nM and 6 ± 3.9 pM for RP 10‐73 and 10‐83, respectively. These two nonlipid compounds lack agonist or antagonist activity at other LPA GPCR up to 10 µM when tested for eliciting or inhibiting ligand‐activated Ca2+ responses. RP 10‐73 and 10‐83 rescued cells from apoptosis induced by ionizing radiation or by the radiomimetic chemotherapeutic agent Adriamycin. The protective effect was not detectable in cells lacking the LPA2 receptor subtype indicating that the antiapoptotic effect requires functional LPA2 receptors in the target cell. The pharmacological properties of RP 10‐73 and 10‐83 make them ideal drug candidates for the specific activation of LPA2 in various disease conditions. Grant Funding Source : Supported by NIAID AI‐107331