mPGES-1 Inhibitors Research Articles

Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing antitumor immunity.

Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells on the immunosuppressive TME is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.

Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92µM and 1.98µM, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.

Insights on Microsomal Prostaglandin E2 Synthase 1 (mPGES-1) Inhibitors using Molecular Dynamics and MM/PBSA Calculations

Background: Despite being a normal body response against invading agents, inflammation, when exaggerated, needs to be controlled to minimize damage to the body. There are several drugs in clinical use against inflammation and other inflammatory conditions. Still, side effects often limit the use of these drugs, such as gastrointestinal effects generated by COX-1 inhibitors and cardiovascular effects by COX-2 inhibitors. Thus, exploring new targets such as mPGES-1 may lead to discovering agents that are more selective against inflammation and generate fewer side effects. Objectives: Here, docking, molecular dynamics, and MM-PBSA studies were performed on a dataset of known mPGES-1 inhibitors to identify helpful information and discover new mPGES-1 inhibitors. Methods: Molecular docking in GOLD software was used to obtain the complexes used in Molecular dynamics simulations (GROMACS software), performed to generate the RMSD, RMSF, Rg, SASA, and H-bond plots to predict the complexes' stability. The most stable conformation was analyzed regarding the most important interactions of the compounds. Finally, MM-PBSA calculations using the tool g_mmpbsa in GROMACS software were performed to determine de-binding affinity, interaction parameters, and per-residue contribution. Results: The main findings of this work were that the molecular dynamics simulation was able to find the open conformation of mPGES-1, which showed a greater preference on compounds in this region, consisting of residues known as "gateways". All compounds showed stability and stable complex formation with mPGES-1, as demonstrated by the results of RMSD, RMSF, Rg, SASA, and H-bond plots generated in a molecular dynamics simulation at 100 ns. The molecular dynamics identified three preferential sites of interaction for the compounds. Thus, the docking and dynamics protocols showed greater affinity of these compounds for cavity-02, interacting with Leu85, Pro81, Gln134, Cys137, Ala138, and Ala141. On the other hand, compound 09 preferred the cavity-03 of the protein, interacting mainly with His72 through Hbond. In addition, MM-PBSA calculations showed binding energies of up to -220,113 KJ/mol for compound 04. Furthermore, MM-PBSA could identify which electrostatic interactions are the most prevalent in the complex formation of the compounds with the highest affinity (04 and 07). Still, the van der Waals interactions are the most important for the others. Finally, the energy contribution per-residue revealed Lys120, Arg122, Arg126, and Tyr130 as the most important for the formation of the complexes. Conclusion: Design mPGES-1 inhibitors based on the residues Leu85, Pro81, Gln134, Cys137, Ala138, and Ala141, in addition to Lys120, Arg122, Arg126, and Tyr130 can provide new promising drugs useful against diseases involving inflammatory conditions.

Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors

Selective inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15–25, 29–30 with IC50 values in the range of 5.6–82.3 nM in a cell-free assay of prostaglandin (PG)E2 formation. We also demonstrate that 20 (TG554, IC50 = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E2 synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E2 (PGE2)—a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE−/− angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

Abstract 4985: Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity

Abstract Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME). Using a genetically engineered mouse model of pancreatic ductal adenocarcinoma, we demonstrate that deleting the terminal PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through cognate EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME to activate T cell immunity and suppress tumor growth. Knockout (KO) of Ptges (the gene encoding PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D/P53R172H/Yfp/CrePd) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner (KO vs control p<0.0001 for both). Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges and Ptger4 KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4 KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected role for autocrine mPGES1-PGE2-EP4 signaling axis in pancreatic cancer cells, nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing approaches in cancer therapy. Citation Format: Nune Markosyan, Ilkyu Kim, Charu Arora, Noah Cheng, Emma Schechter, John Tobias, Ben Stanger, Robert Vonderheide. Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4985.

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Chromone-based small molecules for multistep shutdown of arachidonate pathway: Simultaneous inhibition of COX-2, 15-LOX and mPGES-1 enzymes

As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices. They also showed appreciable 15-LOX inhibition, in comparison to quercetin. Further testing of these compounds for mPGES-1 inhibition displayed promising activities. Intriguingly, compounds 2a-c were capable of suppressing edema in the formalin-induced rat paw edema assay. They exhibited an acceptable gastrointestinal safety profile regarding ulcerogenic liabilities in gross and histopathological examinations. Additionally, upon treatment with the test compounds, the expression of the anti-inflammatory cytokine IL-10 was elevated, whereas that of TNF-α, iNOS, IL-1β, and COX-2 were downregulated in LPS-challenged RAW264.7 macrophages. Docking experiments into the three enzymes showed interesting binding profiles and affinities, further substantiating their biological activities. Their in silico physicochemical and pharmacokinetic parameters were advantageous.

Discovering the Active Ingredients of Medicine and Food Homologous Substances for Inhibiting the Cyclooxygenase-2 Metabolic Pathway by Machine Learning Algorithms.

Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase (mPGES-1) are two key targets in anti-inflammatory therapy. Medicine and food homology (MFH) substances have both edible and medicinal properties, providing a valuable resource for the development of novel, safe, and efficient COX-2 and mPGES-1 inhibitors. In this study, we collected active ingredients from 503 MFH substances and constructed the first comprehensive MFH database containing 27,319 molecules. Subsequently, we performed Murcko scaffold analysis and K-means clustering to deeply analyze the composition of the constructed database and evaluate its structural diversity. Furthermore, we employed four supervised machine learning algorithms, including support vector machine (SVM), random forest (RF), deep neural networks (DNNs), and eXtreme Gradient Boosting (XGBoost), as well as ensemble learning, to establish 640 classification models and 160 regression models for COX-2 and mPGES-1 inhibitors. Among them, ModelA_ensemble_RF_1 emerged as the optimal classification model for COX-2 inhibitors, achieving predicted Matthews correlation coefficient (MCC) values of 0.802 and 0.603 on the test set and external validation set, respectively. ModelC_RDKIT_SVM_2 was identified as the best regression model based on COX-2 inhibitors, with root mean squared error (RMSE) values of 0.419 and 0.513 on the test set and external validation set, respectively. ModelD_ECFP_SVM_4 stood out as the top classification model for mPGES-1 inhibitors, attaining MCC values of 0.832 and 0.584 on the test set and external validation set, respectively. The optimal regression model for mPGES-1 inhibitors, ModelF_3D_SVM_1, exhibited predictive RMSE values of 0.253 and 0.35 on the test set and external validation set, respectively. Finally, we proposed a ligand-based cascade virtual screening strategy, which integrated the well-performing supervised machine learning models with unsupervised learning: the self-organized map (SOM) and molecular scaffold analysis. Using this virtual screening workflow, we discovered 10 potential COX-2 inhibitors and 15 potential mPGES-1 inhibitors from the MFH database. We further verified candidates by molecular docking, investigated the interaction of the candidate molecules upon binding to COX-2 or mPGES-1. The constructed comprehensive MFH database has laid a solid foundation for the further research and utilization of the MFH substances. The series of well-performing machine learning models can be employed to predict the COX-2 and mPGES-1 inhibitory capabilities of unknown compounds, thereby aiding in the discovery of anti-inflammatory medications. The COX-2 and mPGES-1 potential inhibitor molecules identified through the cascade virtual screening approach provide insights and references for the design of highly effective and safe novel anti-inflammatory drugs.

High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance.

High-throughput drug screening enables the discovery of new anticancer drugs. Although monolayer cell cultures are commonly used for screening, their limited complexity and translational efficiency require alternative models. Three-dimensional cell cultures, such as multicellular tumor spheroids (MCTS), mimic tumor architecture and offer promising opportunities for drug discovery. In this study, we developed a neuroblastoma MCTS model for high-content drug screening. We also aimed to decipher the mechanisms underlying synergistic drug combinations in this disease model. Several agents from different therapeutic categories and with different mechanisms of action were tested alone or in combination with selective inhibition of prostaglandin E2 by pharmacological inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). After a systematic investigation of the sensitivity of individual agents and the effects of pairwise combinations, GFP-transfected MCTS were used in a confirmatory screen to validate the hits. Finally, inhibitory effects on multidrug resistance proteins were examined. In summary, we demonstrate how MCTS-based high-throughput drug screening has the potential to uncover effective drug combinations and provide insights into the mechanism of synergy between an mPGES-1 inhibitor and chemotherapeutic agents.

MPGES-1 Inhibitor Discovery Based on Computer-Aided Screening: Pharmacophore Models, Molecular Docking, ADMET, and MD Simulations.

mPGES-1 is an enzyme, which, when activated by inflammatory factors, can cause prostaglandin E synthesis. Traditional non-steroidal anti-inflammatory drugs are capable of inhibiting prostaglandin production, yet they can also cause gastrointestinal reactions and coagulation disorders. mPGES-1, the enzyme at the conclusion of prostaglandin production, does not cause any adverse reactions when inhibited. Numerous studies have demonstrated that mPGES-1 is more abundant in cancerous cells than in healthy cells, indicating that decreasing the expression of mPGES-1 could be a potential therapeutic strategy for cancer. Consequently, the invention of mPGES-1 inhibitors presents a fresh avenue for the treatment of inflammation and cancer. Incorporating a database of TCM compounds, we collected a batch of compounds that had an inhibitory effect on mPGES-1 and possessed IC50 value. Firstly, a pharmacophore model was constructed, and the TCM database was screened, and the compounds with score cut-off values of more than 1 were retained. Then, the compounds retained after being screened via the pharmacodynamic model were screened for docking at the mPGES-1 binding site, followed by high-throughput virtual screening [HTVS] and standard precision [SP] and super-precision [XP] docking, and the compounds in the top 20% of the XP docking score were selected to calculate the total free binding energy of MM-GBSA. The best ten compounds were chosen by comparing their score against the reference ligand 4U9 and the MM-GBSA_dG_Bind score. ADMET analysis resulted in the selection of ten compounds, three of which had desirable medicinal properties. Finally, the binding energy of the target protein mPGES-1 and the candidate ligand compound was analyzed using a 100 ns molecular dynamics simulation of the reference ligand 4U9 and three selected compounds. After a gradual screening study and analysis, we identified a structure that is superior to the reference ligand 4U9 in all aspects, namely compound 15643. Taken together, the results of this study reveal a structure that can be used to inhibit mPGES-1 compound 15643, thereby providing a new option for anti-inflammatory and anti-tumor drugs.

Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion.

Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression. We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.

Iristectorigenin C suppresses LPS-induced macrophages activation by regulating mPGES-1 expression and p38/JNK pathway

Ethnopharmacological relevanceNonsteroidal anti-inflammatory drugs (NSAIDs) have been used clinically to treat inflammatory diseases clinically. However, the adverse effects of NSAIDs cannot be ignored. Therefore, it is critical for us to find alternative anti-inflammatory drugs that can reduce adverse reactions to herbal medicine, such as Iris tectorum Maxim., which has therapeutic effects and can treat inflammatory diseases and liver-related diseases. Aim of the studyThis study aimed to isolate active compounds from I. tectorum and investigate their anti-inflammatory effects and action mechanisms. Materials and methodsFourteen compounds were isolated from I. tectorum using silica gel column chromatography, Sephadex LH-20, ODS and high performance liquid chromatography, and their structures were identified by examining physicochemical properties, ultraviolet spectroscopy, infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Classical inflammatory cell models were established using lipopolysaccharide (LPS)-stimulated RAW264.7 cells and rat primary peritoneal macrophages to examine the effect of these compounds. To examine the action mechanisms, the nitric oxide (NO) levels were measured by Griess reagent and the levels of inflammatory cytokines in the supernatant were measured by ELISA; The expressions of major proteins in prostaglandin E2 (PGE2) synthesis and the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were examined by Western blotting, and the mRNA expression levels were measured by quantitative real-time polymerase chain reaction; and the nuclear translocation of p65 was examined by high content imaging. Molecular docking was used to predict the binding of active compound to target protein. ResultsOur findings revealed that Iristectorigenin C (IT24) significantly inhibited the levels of NO and PGE2 without affecting cyclooxygenase (COX)-1/COX-2 expression in LPS-induced RAW264.7 cells and rat peritoneal macrophages. Furthermore, IT24 was shown to decrease the expression of microsomal prostaglandin synthetase-1 (mPGES-1) in LPS-induced rat peritoneal macrophages. IT24 did not suppress the phosphorylation and nuclear translocation of proteins in the NF-κB pathway, but it inhibited the phosphorylation of p38/JNK in LPS-stimulated RAW264.7 cells. Additionally, molecular docking analysis indicated that IT24 may directly bind to the mPGES-1 protein. ConclusionIT24 might inhibit mPGES-1 and the p38/JNK pathway to exert its anti-inflammatory effects and could be also developed as an inhibitor of mPGES-1 to prevent and treat mPGES-1-related diseases, such as inflammatory diseases, and holds promise for further research and drug development.

2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis

Background2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on...

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders.

The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE2-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE2, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE2 participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE2. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE2 upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE2 have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.

Microsomal prostaglandin E synthase-1 inhibition promotes shunting in arachidonic acid metabolism during inflammatory responses in vitro

Microsomal Prostaglandin E Synthase 1 (mPGES-1) is the key enzyme for the generation of the pro-inflammatory lipid mediator prostaglandin E2 (PGE2), which contributes to several pathological features of many diseases. Inhibition of mPGES-1 has been shown to be a safe and effective therapeutic strategy in various pre-clinical studies. In addition to reduced PGE2 formation, it is also suggested that the potential shunting into other protective and pro-resolving prostanoids may play an important role in resolution of inflammation. In the present study, we analysed the eicosanoid profiles in four in vitro inflammation models and compared the effects of mPGES-1 inhibition with those of cyclooxygenase-2 (Cox-2) inhibition. Our results showed a marked shift to the PGD2 pathway under mPGES-1 inhibition in A549 cells, RAW264.7 cells and mouse bone marrow-derived macrophages (BMDMs), whereas enhanced prostacyclin production was observed in rheumatoid arthritis synovial fibroblasts (RASFs) treated with an mPGES-1 inhibitor. As expected, Cox-2 inhibition completely suppressed all prostanoids. This study suggests that the therapeutic effects of mPGES-1 inhibition may be mediated by modulation of other prostanoids in addition to PGE2 reduction.

Novel, Brain-Permeable, Cross-Species Benzothiazole Inhibitors of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Dampen Neuroinflammation In Vitro and In Vivo.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme of the cyclooxygenase (COX) cascade that generates prostaglandin E2 (PGE2) during inflammatory conditions. PGE2 is known to be a potent immune signaling molecule that mediates both peripheral and central inflammations. Inhibition of mPGES-1, rather than COX, may overcome the cardiovascular side effects associated with long-term COX inhibition by providing a more specific strategy to target inflammation. However, mPGES-1 inhibitor development is hampered by the large differences in cross-species activity due to the structural differences between the human and murine mPGES-1. Here, we report that our thiazole-based mPGES-1 inhibitors, compounds 11 (UT-11) and 19 derived from two novel scaffolds, were able to suppress PGE2 production in human (SK-N-AS) and murine (BV2) cells. The IC50 values of inhibiting PGE2 production in human and murine cells were 0.10 and 2.00 μM for UT-11 and 0.43 and 1.55 μM for compound 19, respectively. Based on in vitro and in vivo pharmacokinetic data, we selected UT-11 for evaluation in a lipopolysaccharide (LPS)-induced inflammation model. We found that our compound significantly suppressed proinflammatory cytokines and chemokines in the hippocampus but not in the kidney. Taken together, we demonstrated the potential of UT-11 in treating neuroinflammatory conditions, including epilepsy and stroke, and warrant further optimization.

Microsomal prostaglandin E synthase-1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice.

Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase-2, affects chronic cardiac remodelling after MI. Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES-1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase-2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography-tandem mass spectrometry. Chronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis-related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of PGI2 , not thromboxane B2 or PGD2 , after inhibition of mPGES-1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary PGI2 /PGE2 metabolite ratio compared to vehicle or celecoxib. The PGI2 /PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function. Inhibition of mPGES-1 prevented chronic adverse cardiac remodelling via an augmented PGI2 /PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI.

Analgesic effects of a highly selective mPGES-1 inhibitor

The growing opioid use and overdose crisis in the US is closely related to the abuse of pain medications. Particularly for postoperative pain (POP), ~ 310 million major surgeries are performed globally per year. Most patients undergoing surgical procedures experience acute POP, and ~ 75% of those with POP report the severity as moderate, severe, or extreme. Opioid analgesics are the mainstay for POP management. It is highly desirable to develop a truly effective and safe non-opioid analgesic to treat POP and other forms of pain. Notably, microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) was once proposed as a potentially promising target for a next generation of anti-inflammatory drugs based on studies in mPGES-1 knockouts. However, to the best of our knowledge, no studies have ever been reported to explore whether mPGES-1 is also a potential target for POP treatment. In this study, we demonstrate for the first time that a highly selective mPGES-1 inhibitor can effectively relieve POP as well as other forms of pain through blocking the PGE2 overproduction. All the data have consistently demonstrated that mPGES-1 is a truly promising target for treatment of POP as well as other forms of pain.