Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

Futatsugi, Kentaro; Smith, Aaron; Tu, Meihua; Raymer, Brian; Ahn, Kay; Coffey, Steven B.; Dowling, Matthew S.; Fernando, Dilinie P.; Gutierrez, Jemy A.; Huard, Kim; Jasti, J.; Kalgutkar, Amit S.; Knafels, John D.; Pandit, Jayvardhan; Parris, Kevin; Perez, Sylvie; Pfefferkorn, Jeffrey A.; Price, David A.; Ryder, Tim F.; Shavnya, Andre; Stock, Ingrid A.; Tsai, Andy S.; Tesz, Gregory J.; Thuma, Benjamin A.; Weng, Yan; Wisniewska, Hanna M.; Xing, Gang; Zhou, Jun; Magee, Thomas V.

doi:10.1021/acs.jmedchem.0c00944

Cited by 51 publications

(46 citation statements)

References 31 publications

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“…Fructose may also directly or indirectly induce hepatic insulin resistance leading to hyperinsulinemia, which can further stimulate hepatic lipogenesis [48]. Ketohexokinase inhibition by PF-06835919 improved NASH by reducing fructose-induced steatosis, fibrogenesis, and liver injury in mouse and human liver cell cultures [49,50]. PF-06835919 administration to NAFLD subjects showed a reduction in hepatic fat content and insulin resistance, ALT, AST, and gamma-glutamyl transferase (GGT) [51].…”

Section: Ketohexokinase Inhibitormentioning

confidence: 99%

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

et al. 2022

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Section: Ketohexokinase Inhibitormentioning

confidence: 99%

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

et al. 2022

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“…Pharmacological inhibition of KHK activity with PF-06835919 is reported to prevent patients from hepatic steatosis, lipogenic, and fibrosis ( Shepherd et al, 2021 ). KHK deficiency or inhibition (PF-06835919) protects animals from fructose-induced obesity, insulin resistance, hypertriglyceridemia, and NAFLD ( Lanaspa et al, 2013 ; Futatsugi et al, 2020 ; Gutierrez et al, 2021 ). Knockout KHK could also decrease fructose-derived UA production and attenuate mitochondrial oxidative stress in mice ( Ishimoto et al, 2012 ).…”

Section: Possible Drug Targets In Fructose Metabolismmentioning

confidence: 99%

The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease

Yu¹,

Li²,

Ji³

et al. 2021

Front. Pharmacol.

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Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger the de novo lipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.

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“…Ketohexokinase (KHK), also known as hepatic fructokinase, catalyses the first step in the metabolism of dietary fructose, comprising the conversion of fructose to fructose-1-phosphate, with the potential to decrease DNL. The KHK inhibitor PF-06835919 reduced hepatic fat and improved insulin resistance in individuals with NAFLD [128,129].…”

Section: Drugs That Modulate Lipid Metabolic Pathwaysmentioning

confidence: 99%

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

2021

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The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium–glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance. Graphical abstract

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Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

Cited by 51 publications

References 31 publications

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

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