mPGES-1 is the terminal enzyme one-step downstream of COX2. It also is the unstable peroxide intermediate from arachidonate catabolism. mPGES-1 can be induced by various inflammatory stimuli in normal cells, or in cells from in vivo disease models.
mPGES-1 closely relates to the production of PGE2 inflammatory conditions. For example, mPGES-1-deleted cells produce significantly lower levels of PGE2. Additionally, mPGES-1 knockout (KO) mice mostly are insensitive to the inflammatory and neuropathic pain.
In this article, we will describe a novel mPGES-1 inhibitor, PF-9184.
PF-9184 inhibits IL-1β-induced PGE2 synthesis in vitro. Firstly, PF-9184 inhibits IL-1β-stimulated prostaglandin E2 (PGE2) synthesis in rheumatoid arthritis (RASF) in synovial fibroblasts derived from patients. It also has no apparent cytotoxic effects up to 100 μM.
PF‐9184 decreases PGE2 biosynthesis by RA synovial fibroblasts induced with IL‐1β. this inhibitor has a direct effect on mPGES‐1 activity. It can significantly decrease PGE2 generation while upregulates PGI2 and PGF2α levels.
Furthermore, in the unstimulated-human whole blood assays，mPGES-1 expression is at very low levels, PF9184 has no effect on PGE2 and TXB2 synthesis.
Remarkably, the addition to the unstimulated blood of 1483 cells, they can express mPGES-1 and COX-2 constitutively. It can restore the ability of PF9184 to inhibit PGE2 synthesis while still sparing TXB2 synthesis.
PF-9184 potently blocks mPGES-1 ability to synthesize PGE2 from PGH2 and with no apparent inhibitory effects on COX-2 and prostacyclin synthase in cells. However, Even PF-9184 inhibits PGE2 weakly but has no effect on TXB2 synthesis except at 100 μM in human whole blood and modified blood assays.
PF-9184 is a potent inhibitor of mPGES-1 function but is not its expression. In Vitro, PF-9184 can inhibit the synthesis of PGE2 but while sparing PGF1a, PGF2a, and TXB2 synthesis.
In conclusion, PF-9184 is a selective mPGES-1 inhibitor and plays an important role in vitro and in vivo.
Reference:
Gabriel M, et, al. Biochem Pharmacol. 2010 May 15; 79(10): 1445-54.