Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening

Identification of new microsomal prostaglandin E-2 synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (similar to 30% inhibition at 10 mu M). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC50 = 4.6 +/- 0.2 mu M for 15; IC50 = 2.4 +/- 1.0 mu M for 20; IC50 = 2.4 +/- 0.8 mu M for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties. (C) 2016 Elsevier Masson SAS. All rights reserved.