Identification of new microsomal prostaglandin E2 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 (∼30% inhibition at 10 μM). 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 μM for 15; 2.4 ± 1.0 μM for 20; IC50 = 2.4 ± 0.8 μM 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.

Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from fragment Virtual Screening / Lauro, Gianluigi; Manfra, Michele; Pedatella, Silvana; Fischer, Katrin; Cantone, Vincenza; Terracciano, Stefania; Bertamino, Alessia; Ostacolo, Carmine; GOMEZ MONTERREY, ISABEL MARIA; De Nisco, Mauro; Riccio, Raffaele; Novellino, Ettore; Werz, Oliver; Campiglia, Pietro; Bifulco, Giuseppe. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 125:5(2017), pp. 278-287. [10.1016/j.ejmech.2016.09.042]

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

PEDATELLA, SILVANA
Investigation
;
OSTACOLO, CARMINE
Investigation
;
GOMEZ MONTERREY, ISABEL MARIA
Conceptualization
;
NOVELLINO, ETTORE
Writing – Original Draft Preparation
;
2017

Abstract

Identification of new microsomal prostaglandin E2 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 (∼30% inhibition at 10 μM). 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 μM for 15; 2.4 ± 1.0 μM for 20; IC50 = 2.4 ± 0.8 μM 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.
2017
Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from fragment Virtual Screening / Lauro, Gianluigi; Manfra, Michele; Pedatella, Silvana; Fischer, Katrin; Cantone, Vincenza; Terracciano, Stefania; Bertamino, Alessia; Ostacolo, Carmine; GOMEZ MONTERREY, ISABEL MARIA; De Nisco, Mauro; Riccio, Raffaele; Novellino, Ettore; Werz, Oliver; Campiglia, Pietro; Bifulco, Giuseppe. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 125:5(2017), pp. 278-287. [10.1016/j.ejmech.2016.09.042]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/645601
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