mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2levels induced by inflammatory stimuli, with neither affecting PGE2constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug–like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities.

Discovery of new potent molecular entities able to inhibit mPGES-1

Di Micco, Simone;Terracciano, Stefania;Cantone, Vincenza;Foglia, Antonio;Riccio, Raffaele;Bruno, Ines
;
Bifulco, Giuseppe
2018

Abstract

mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2levels induced by inflammatory stimuli, with neither affecting PGE2constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug–like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities.
File in questo prodotto:
File Dimensione Formato  
2018_EuropeanJMedChem_mpges1.pdf

non disponibili

Descrizione: mpges1
Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 1.37 MB
Formato Adobe PDF
1.37 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4704815
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 23
social impact