Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1,6-bisphosphatase with a distinct binding mode

Geldern, Thomas W von; Lai, Chunqiu; Gum, Rebecca J.; Daly, Melissa; Sun, Chaohong; Fry, Elizabeth H.; Abad‐Zapatero, Celerino

doi:10.1016/j.bmcl.2006.01.015

Cited by 47 publications

(24 citation statements)

References 18 publications

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“…FBPase transgenic mice, negative littermate controls (∼16 weeks old), and NZO mice (7 weeks old) were gavaged daily a 5 mg/kg dose of benzoxazole benzene sulfonamide, a commercially available human-specific FBPase inhibitor (Calbiochem) (18,19), to specifically target our construct or vehicle (water) 2 h before the dark cycle (feeding period) for 10 days. Body weight and food intake measurements were taken daily.…”

Section: Methodsmentioning

confidence: 99%

The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

et al. 2012

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Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-β-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation.

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Section: Methodsmentioning

confidence: 99%

The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

et al. 2012

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“…In light of this data, FBPase has recently received interest from pharmaceutical companies producing compounds to inhibit FBPase as a target for type 2 diabetes therapy (10,16,44,45). These inhibitors decrease EGP in Zucker diabetic fatty rats, an obese diabetic animal model (10,44), demonstrating a potential therapeutic benefit of FBPase inhibitor compounds for type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver

Visinoni¹,

Fam²,

Blair³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Increased endogenous glucose production (EGP) predominantly from the liver is a characteristic feature of type 2 diabetes, which positively correlates with fasting hyperglycemia. Gluconeogenesis is the biochemical pathway shown to significantly contribute to increased EGP in diabetes. Fructose-1,6-bisphosphatase (FBPase) is a regulated enzyme in gluconeogenesis that is increased in animal models of obesity and insulin resistance. However, whether a specific increase in liver FBPase can result in increased EGP has not been shown. The objective of this study was to determine the role of upregulated liver FBPase in glucose homeostasis. To achieve this goal, we generated human liver FBPase transgenic mice under the control of the transthyretin promoter, using insulator sequences to flank the transgene and protect it from site-of-integration effects. This resulted in a liver-specific model, as transgene expression was not detected in other tissues. Mice were studied under the following conditions: 1) at two ages (24 wk and 1 yr old), 2) after a 60% high-fat diet, and 3) when bred to homozygosity. Hemizygous transgenic mice had an approximately threefold increase in total liver FBPase mRNA with concomitant increases in FBPase protein and enzyme activity levels. After high-fat feeding, hemizygous transgenics were glucose intolerant compared with negative littermates ( P < 0.02). Furthermore, when bred to homozygosity, chow-fed transgenic mice showed a 5.5-fold increase in liver FBPase levels and were glucose intolerant compared with negative littermates, with a significantly higher rate of EGP ( P < 0.006). This is the first study to show that FBPase regulates EGP and whole body glucose homeostasis in a liver-specific transgenic model. Our homozygous transgenic model may be useful for testing human FBPase inhibitor compounds with the potential to treat patients with type 2 diabetes.

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“…AMP ( 1 ), Achyrofuran ( 2 ), (+)-Usnic acid ( 3 ), Inhibitors ( 4 ) [13], ( 5 ), ( 6 ) [35], ( 7 ) [36], ( 8 ) [37], ( 9 ) [11] and ( 10 ) [12] are known inhibitors of FBPase that were docked against the enzyme using GLIDE.…”

Section: Figures and Tablementioning

confidence: 99%

“…However, they found that these anilinoquinazolines bound to a ‘novel allosteric site’. Another class of inhibitors identified by a high-throughput screen (HTS), which also bind to the ‘novel allosteric site’, is a group of benzoxazole-2-benzene-sulfonamides [11]. Other small-molecule inhibitors, which bind to the allosteric site of FBPase and are competitive with the binding of AMP, include MB05032 [12] and 3-(2-carboxy-ethyl)-4,6-dichloro-1H-indole-2-carboxylic acid [13].…”

Section: Introductionmentioning

confidence: 99%

Designing inhibitors against fructose 1,6-bisphosphatase: Exploring natural products for novel inhibitor scaffolds

Heng

Harris

Kantrowitz

2010

European Journal of Medicinal Chemistry

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Natural products often contain unusual scaffold structures that may be elaborated by combinatorial methods to develop new drug-like molecules. Visual inspection of more than 128 natural products with some type of anti-diabetic activity suggested that a subset might provide novel scaffolds for designing potent inhibitors against fructose 1,6-bisphosphatase (FBPase), an enzyme critical in the control of gluconeogenesis. Using in silico docking methodology, these were evaluated to determine those that exhibited affinity for the AMP binding site. Achyrofuran from the South American plant Achyrocline satureoides, was selected for further investigation. Using the achyrofuran scaffold, inhibitors against FBPase were developed. Compounds 15 and 16 inhibited human liver and pig kidney FBPases at IC 50 values comparable to that of AMP, the natural allosteric inhibitor.

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Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1,6-bisphosphatase with a distinct binding mode

Cited by 47 publications

References 18 publications

The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver

Designing inhibitors against fructose 1,6-bisphosphatase: Exploring natural products for novel inhibitor scaffolds

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