Identification and Development of Mpges-1 Inhibitors: Where We are At?

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal synthase responsible for the synthesis of the pro-tumorigenic prostaglandin E2 (PGE2). mPGES-1 is overexpressed in a wide variety of cancers. Since its discovery in 1997 by Bengt Samuelsson and collaborators, the enzyme has been the object of over 200 peer-reviewed articles. Although today mPGES-1 is considered a validated and promising therapeutic target for anticancer drug discovery, challenges in inhibitor design and selectivity are such that up to this date there are only a few published records of small-molecule inhibitors targeting the enzyme and exhibiting some in vivo anticancer activity. This review summarizes the structures, and the in vitro and in vivo activities of these novel mPGES-1 inhibitors. Challenges that have been encountered are also discussed.

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

“…Among three PGE2 synthases, only mPGES-1 has been proved to have the ability in producing PGE2 in vivo [14, 21], and is thought as the most promising target of next generation of anti-inflammatory drugs [38, 39]. As a downstream enzyme of COX, it is possible that the mPGES-1 inhibitors may preserve less adverse effects than the COX inhibitors in treating the inflammatory diseases.…”

Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes

“…The above mentioned combination is also recommended in the A selective inhibition of PGE 2 formation might be an effective manner to treat many types of pain with less adverse effects as compared to NSAIDs. Intensive research on mPGES-1 inhibitors has been ongoing since the enzyme was characterized, and many compounds with different molecular structures seem to inhibit it, but a specific inhibitor appliable for clinical use is yet to be discovered (5,(21)(22)(23)(24). Another approach to reduce PGE 2 production especially in inflammatory conditions might be down-regulation of mPGES-1 expression and according to the present findings that is achieved by using aurothiomalate but not with the other commonly used DMARDs.…”

Discovery and characterization of a potent and selective EP4 receptor antagonist

“…Homologation of the benzylic substituent (7) did not improve the potency, nor did incorporation of a second substituent in the form of a 1,1-cyclopropane (8). Addition of a cyano substituent at the para position of the phenoxy ring (9) had a detrimental effect on potency; however, 4-fluoro analogue 10 performed similarly to 6 in all three assays.…”