PF-06835919

PF-06835919 is an inhibitor of ketohexokinase C (KHK-C; IC₅₀ = 10 nM).¹ It is selective for KHK-C over KHK-A (IC₅₀ = 170 nM) and a panel of 89 kinases, phosphatases, and receptors at 10 µM. PF-06835919 decreases the levels of fructose-1-phosphate in primary human- and rat hepatocytes (IC₅₀s = 0.232 and 2.801 µM, respectively).² It inhibits glucose- and fructose-induced nuclear translocation of carbohydrate-responsive element-binding protein (ChREBP) in a reporter assay using primary rat hepatocytes when used at a concentration of 30 µM. PF-06835919 (10 or 30 mg/kg twice per day) reduces the weight of epididymal adipose tissue, fasting plasma levels of insulin, hepatic levels of triglycerides, and fed- and fasting plasma levels of triglycerides and increases urinary levels of fructose in rats fed a high-fructose diet. It decreases plasma levels of apolipoprotein C3 (ApoC3) and increases plasma levels of adiponectin in rats fed a Western diet when administered at doses of 20 or 60 mg/kg per day.

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1. Futatsugi, K., Smith, A., Tu, M., et al. Discovery of PF-06835919: A potent inhibitor of ketohexokinase (KHK) for the treatment of metabolic disorders driven by the overconsumption of fructose. J. Med. Chem. 63(22), 13546-13560 (2020).

2. Gutierrez, J.A., Liu, W., Perez, S., et al. Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction. Mol. Metab. 48, 101196 (2021).