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

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

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.676631

DOI=10.3389/fchem.2021.676631

ISSN=2296-2646

ABSTRACT=<p>We report the implementation of our <italic>in silico</italic>/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 <bold>1c</bold> and <bold>2c</bold> showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, <bold>1c</bold> and <bold>2c</bold> exhibited interesting IC<sub>50</sub> values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound <bold>2c</bold> induced the cycle arrest in the G<sub>0</sub>/G<sub>1</sub> phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG<sub>0</sub>/G<sub>1</sub> fraction, suggesting an apoptosis/necrosis effect.</p>