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

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.

Repositioning of Quinazolinedione-Based Compounds on Soluble Epoxide Hydrolase (sEH) through 3D Structure-Based Pharmacophore Model-Driven Investigation

“…In the last few years, our research group has been involved in the discovery of novel soluble epoxide hydrolase inhibitors (sEHi) and, accordingly, the development of sEH 3D structure-based pharmacophore model represents a valuable strategy for accomplishing this aim [20,21]. Indeed, in addition to the identification of novel compounds with anti-inflammatory and anticancer activity targeting mPGES-1, representing another key target of our research interests [20,[22][23][24], we also focused on other targets belonging to the arachidonic acid cascade to identify multitarget agents with greater benefits than single-target inhibition [25]. In light of these premises, the 3D structure-based pharmacophore model was developed by collecting the necessary spatial definitions from the specific coordinates of multiple co-crystallized inhibitors in the specific sEH binding site, obtaining a model directly placed in the pocket cavity of the enzyme, bearing the 3D information from multiple known co-crystallized inhibition.…”

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-β/Smad3 and PI3K/AKT signal pathways

“…Firstly, only one inhibitor of mPGES1, CAY10526, was used. However, its efficacy and selectivity on mPGES1 has been confirmed (15)(16)(17) including in our previous report (7), and was even employed as reference compound (18). Experiments are currently undergoing including knock down of mPGES-1 by RNA silencing and exogenous PGE2 supplement for rescue.…”

“…Based on this preliminary finding, we chose CAY10526 (CAS:938069-71-7) to treat Hut78 cells. As several studies have shown that CAY10526 is an isoformselective inhibitor of PGE2 production through the selective modulation of mPGES-1 expression (15)(16)(17), and was even selected as reference compound when newer compound was synthesized and tested (18). The dose of CAY10526 used in the studies ranged from 1.8 to 300 μM for different cells and experimental conditions, including our previous report showing CAY10526 [half inhibitory concentration (IC50): 16.7 μM at 24 h] reduced PGE2 synthesis in primary T-cell acute lymphoblastic leukemia (T-ALL) cells (7).…”

Extensive Molecular Dynamics Simulations Disclosed the Stability of mPGES‐1 Enzyme and the Structural Role of Glutathione (GSH) Cofactor

“…Furthermore, the comparison of X‐ray structures of mPGES‐1 bound to GSH (PDB ID: 4AL0) [12] and its analogue (PDB code: 4AL1), [12] presenting a bulky biphenyl substituent, highlighted no significant conformational changes except a slight shift of Y130 residue. Also, the superposition of further mPGES‐1 structures co‐complexed with small molecules confirmed this outcome [13−15] …”