title: 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.
authors.affiliation: Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, Republic of Korea.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Park
authors.forename: Seong-Gu
authors.initials: SG
authors.lastname: Han
authors.forename: Hafiz Muhammad
authors.initials: HM
authors.lastname: Ahsan
authors.forename: Kijae
authors.initials: K
authors.lastname: Lee
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Nam-Suk
authors.initials: NS
authors.lastname: Kang
authors.forename: Yeon Gyu
authors.initials: YG
authors.lastname: Yu
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D054852:Small Molecule Libraries; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone