Identification of 2,4-Dinitro-Biphenyl-Based Compounds as MAPEG Inhibitors

Abstract

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C₄ synthase (LTC₄ S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC₄ S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E₂ synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment.

Keywords: FLAP inhibitors; LTC4S inhibitors; anti-inflammatory drugs; anticancer agents; multitargeting approach.