Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition.

Simone Di Micco,Stefania Terracciano,Oliver Werz,Giuseppe Bifulco,Dafne Ruggiero,Marianna Potenza,Maria C Vaccaro,Ines Bruno,Katrin Fischer

doi:10.3389/fchem.2021.676631

Abstract

We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC50 values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G0/G1 phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG0/G1 fraction, suggesting an apoptosis/necrosis effect.

Highlights

We reported the successful identification of new mPGES-1 (Microsomal prostaglandin E synthase-1) inhibitors endowed with 1-fluoro-2,4-dinitro-biphenyl scaffold (Di Micco et al, 2018), acting in the low micromolar range in cell-free assays
These structural considerations are fully supported by x-ray crystallography (Sjçgren et al, 2013; Li et al, 2014; Luz et al, 2015; Kuklish et al, 2016; Schiffler et al, 2016; Partridge et al, 2017), showing that the inhibitors bound to mPGES-1 give π-π interactions with Tyr28 and Tyr130 and van der Waals contacts with the other residues outlining the transmembrane cavity
By combining a virtual fragment-based approach and biological investigations in cell-free and cell-based assays, we succeeded in identifying the 4-phenyl-(thiophen-2-yl)acetic acid-based compound 2c as a novel lead compound worthy to progressively develop new-generation m-PGES-1 inhibitors with anti-tumoral and/or anti-inflammatory properties

Summary

Introduction

We reported the successful identification of new mPGES-1 (Microsomal prostaglandin E synthase-1) inhibitors endowed with 1-fluoro-2,4-dinitro-biphenyl scaffold (Di Micco et al, 2018), acting in the low micromolar range in cell-free assays. Its inhibition selectively affects the PGE2 upregulated by pathological conditions, while keeping the tissue levels of other important prostanoid molecules (Trebino et al, 2003), which are responsible for key cellular physiological functions This special feature allows circumventing the typical gastrointestinal and cardiovascular side effects of COX-1/2 and selective COX2 inhibitors (Di Micco et al, 2016). The discovery of new promising chemotypes, hopefully endowed with cross-species activity, for clinical practice is highly requested In this scenario, many efforts have been made by our research group in order to gain insights into the structural requirements needed to assure an optimal interaction between a ligand and the biological target under investigation (Di Micco et al, 2016, 2018; Gerstmeier et al, 2019; Chini et al, 2020). With a promising anti-MPGES-1 activity, have been identified and are currently under further investigation to deepen their biological and pharmacological profile

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Results

Conclusion