Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Abstract

The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

CES2 sustains HNF4α expression to promote pancreatic adenocarcinoma progression through an epoxide hydrolase-dependent regulatory loop

“…Prior studies on other cancer types have demonstrated the anticancer effects of fenofibrate [ 49 ]. Small-molecule inhibition of sEH via Trans-AUCB similarly reduced PDAC cell viability, consistent with prior studies on other cancer types [ [50] , [51] , [52] , [53] ]. Notably, in our study, the combination of fenofibrate plus trans -AUCB yielded improved anticancer effects compared with either treatment alone.…”

2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity

“…MeOH (1 mL) and KOH (116 mg, 2.07 mmol) were added, and the mixture was stirred at 50 • C for 4 h. Amberlite ® 120 H+ was added until pH = 4 and the mixture was filtered, using MeOH as an eluting agent. Solvents were concentrated in vacuo to afford a white solid that was purified by column chromatography in silica gel (SiO 2 , DCM/MeOH mixtures) and gave 10d as a reddish solid (16 To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo [9] annulen-7-amine (88 mg, 0.36 mmol), 2e, in DMF (2 mL), 2-(1-(4-(t-butoxycarbonyl)phenyl) piperidin-4-yl)acetic acid (125 mg, 0.39 mmol), 9c, HATU (203 mg, 0.53 mmol), and DIPEA (124 µL, 92 mg, 0.71 mmol) were added. The mixture was stirred at room temperature overnight.…”

“…Taking into account that several adamantane-based and benzene-based ureas are endowed with very potent activity as sEHI [14][15][16][17], that both AR9281 and EC5026 feature an acylpiperidine unit, and that the highly hydrophobic pocket of sEH seems able to accommodate very large hydrophobic groups [18], we have recently designed, synthesized and pharmacologically evaluated a novel series of ureas featuring the benzohomoadamantane scaffold as hydrophobic moiety, that merges in its polycyclic structure an adamantane-related core with an aromatic ring [19]. Several of these novel sEHI-based ureas were low nanomolar inhibitors of the human and murine sEH, but most of them, as 1, showed high melting points, limited solubility, and unacceptably low microsomal stabilities (Figure 2) [19].…”

Eicosanoid regulation of debris-stimulated metastasis

“…Because EETs are rapidly metabolized by soluble epoxide hydrolase (sEH) to the less active dihydroxyeicosatrienoic acids (DiHETEs) ( 62 ), inhibition of sEH stabilizes EETs ( 62 , 65 ). Indeed, sEH is a key therapeutic target for pain, as well as neurodegenerative and inflammatory diseases, including cancer ( 33 , 35 , 65 – 74 ). Thus, sEH regulates inflammatory responses ( 62 ).…”

“…Chronic pancreatitis is essential for the induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice, suggesting that inflammation is a critical driver of pancreatic cancer ( 76 , 77 ). Potent, selective inhibitors of sEH have been demonstrated to suppress human cancers (e.g., glioblastoma) and inflammation-induced carcinogenesis ( 67 , 71 ). Similarly, inhibition of sEH can suppress inflammatory bowel disease-induced carcinogenesis and inflammation-associated pancreatic cancer ( 74 , 78 ).…”