Identification of novel mPGES-1 inhibitors through screening of a chemical library

Abstract

Human microsomal prostaglandin E synthase-1 (mPGES-1) is an emerging drug target for inflammatory disorders and cancer suppression. Therefore, it is crucially important to discover mPGES-1 inhibitors with novel structural scaffolds for the development of anti-inflammatory drugs. Here, we report the mPGES-1 inhibitors identified through screening of a chemical library. Initial screening of 1841 compounds out of 200,000 in a master library resulted in 9 primary hits. From the master library, 387 compounds that share the scaffold structure with the 9 primary hit compounds were selected, of which 3 compounds showed strong inhibitory activity against mPGES-1 having IC(50) values of 1-3 μM. Notably, a derivative of sulfonylhydrazide, compound 3b, inhibited the LPS-induced PGE(2) production in RAW 264.7 cells. This compound showed novel scaffold structure compared to the known inhibitors of mPGES-1, suggesting that it could be further developed as a potent mPGES-1 inhibitor.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…The screening of compound libraries has permitted the further identification of a wide variety of promising scaffolds to design potent and selective mPGES‐1 inhibitors, namely, (Z)‐5‐benzylidene‐2‐iminothiazolidin‐4‐one, aminothiazole, triazole, s‐triazine, benzenesulfonamide, trisubstituted urea, sulfonylhydrazide, carbazole benzamide, and pyrazolone . In some cases, in vivo experiments have demonstrated the potential effectiveness of these mPGES‐1 inhibitors to treat inflammatory conditions.…”

Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol

“… 29 In addition, several active compounds were discovered by applying docking-based screening strategies, of which some even elicited high potency. 30–33 Docking-based virtual screening campaigns towards mPGES-1 have been facilitated as a 3D electron crystallography structure was reported in 2008. 34 In 2013, a high-resolution X-ray crystal structure of mPGES-1 has been resolved.…”

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders

“…These compounds are characteristic of their compatibility in selectively and potently inhibiting both human and murine mPGES-1 without intervening in the activities of COX enzymes. 8,39,79,80 Our recent publication highlighted the enhanced dualspecies activity of our lead compound UT-11, over its predecessor C3 at inhibiting mPGES-1 mediated inflammation both in vitro and in vivo. Compounds were screen in vitro and tested in vivo for their efficacy at suppressing mPGES-1 mediated inflammation, following stimulation with lipopolysaccharide (LPS).…”