The Par2 Inhibitor I-287 Selectively Targets G Alpha(Q) And G Alpha(12/13) Signaling And Has Anti-Inflammatory Effects

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on G alpha (q) and G alpha (12/13) activity and their downstream effectors, while having no effect on G(i/o) signaling and beta arrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor. Avet et al. characterize I-287, an inhibitor to protease-activated receptor 2 using BRET-assays. They find that I-287 selectively inhibits G alpha (q) and G alpha (12/13) without affecting the activation of G(i/o) or the recruitment of beta arrestin2 and that it blocks inflammation in vitro and in vivo.