Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

Futatsugi, Kentaro; Kung, Daniel W.; Orr, Suvi T. M.; Cabral, Shawn; Hepworth, David; Aspnes, Gary E.; Bader, Scott J.; Bian, Jianwei; Boehm, Markus; Carpino, Philip A.; Coffey, Steven B.; Dowling, Matthew S.; Herr, Michael; Jiao, Wenhua; Lavergne, Sophie Y.; Li, Qifang; Clark, Ronald W.; Erion, Derek M.; Kou, Kou; Lee, Kyuha; Pabst, Brandon; Perez, Sylvie; Purkal, Julie J.; Jorgensen, Csilla C.; Goosen, Theunis C.; Gosset, J; Niosi, Mark; Pettersen, John C.; Pfefferkorn, Jeffrey A.; Ahn, Kay; Goodwin, Bryan

doi:10.1021/acs.jmedchem.5b01006

Cited by 65 publications

(84 citation statements)

References 61 publications

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“…Moreover, microsomes from cells stably expressing (Figure 4I, inset) catalytically inactive DGAT2 (Stone et al, 2006) did not have activity towards acylceramide generation (Figure 4I). Furthermore, acylceramide generation was prevented by the DGAT2 specific inhibitor PF-06424439 (Futatsugi et al, 2015) in a dose dependent manner in vitro (Figure 4J). Belonging to a MBOAT family, distinct from DGAT2, DGAT1 was shown to have DGAT, MGAT, and wax ester synthase activities (Yen et al, 2005a; Yen et al, 2005b), therefore we tested the ability of DGAT1 to generate acylceramide in vitro .…”

Section: Resultsmentioning

confidence: 99%

“…C57BL/6 mice were fed either a control (12.6% calories from fat; TD.05230) or a diet enriched with oleate (41.7% calories from fat; TD.140589) for four or eight weeks and euthanized prior to tissue collection. PF-064244399 (PF) treatment of mice was carried out as described (Futatsugi et al, 2015). Briefly, at the end of the 8 weeks of oleate HFD, mice were treated with vehicle (0.5 % methylcellulose) or PF at a dose of 30 mg/kg BID for 4 days (7 doses).…”

Section: Methodsmentioning

confidence: 99%

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Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

et al. 2017

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SUMMARY In an approach aimed at defining interacting partners of ceramide synthases (CerS), we found that fatty acyl CoA synthase ACSL5 interacts with all CerS. We demonstrate that ACSL5 generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LD in cells and in livers of mice on a high fat diet. The study also implicates this novel pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

et al. 2017

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“…Viruses such as HCV and rotavirus that are sensitive to inhibition by Triacsin C are also impaired by inhibitors of DGATs 14,31 . Therefore, we tested the effects of DGAT1 and DGAT2 inhibitors T863 and PF06424439 32,33 . Neither compound displayed any inhibitory activity (Supplemental Figure 1).…”

Section: Inhibition Of Fatty Acid Metabolism Inhibits Sars-cov-2 Replmentioning

confidence: 99%

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Silvas

Jureka

Nicolini

et al. 2020

Preprint

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Therapeutics targeting replication of SARS coronavirus 2 (SARS-CoV-2) are urgently needed. Coronaviruses rely on host membranes for entry, establishment of replication centers and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we tested small molecule inhibitors that target membrane dynamics or lipid metabolism. Included were inhibitors of the PI3 kinase VPS34, which functions in autophagy, endocytosis and other processes; Orlistat, an inhibitor of lipases and fatty acid synthetase, is approved by the FDA as a treatment for obesity; and Triacsin C which inhibits long chain fatty acyl-CoA synthetases. VPS34 inhibitors, Orlistat and Triacsin C inhibited virus growth in Vero E6 cells and in the human airway epithelial cell line Calu-3, acting at a post-entry step in the virus replication cycle. Of these the VPS34 inhibitors exhibit the most potent activity.

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“…5 Pre-clinically, beneficial metabolic phenotypes of DGAT2 inhibition have been demonstrated by antisense oligonucleotide studies 6 and more recently with small molecule inhibitors. 7 It was also shown that MGAT2-deficient mice are protected against diet-induced obesity, glucose intolerance and fatty liver 8 and MGAT2 inhibitors have been reported in the literature. 9…”

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confidence: 96%

Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3

et al. 2015

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Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.

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Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

Cited by 65 publications

References 61 publications

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3

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