PF-06835919

Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer's virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.

Fructose is a simple carbohydrate present in fruits and honey. It is also present in soft drinks as sucrose (a disaccharide of fructose and glucose) and in high fructose corn syrup (mainly used in sodas). Fructose intake has considerably increased in past decades in parallel with the consumption of sugar-sweetened beverages. Although the main source of fructose is alimentation, endogenous production of fructose can also occur under certain circumstances including ischemia, hyperosmolarity, or hyperglycemia. Even if fructose production is low, it can increase during diabetes, with a high carbohydrate diet, or with alcohol consumption. Both experimental and epidemiological data support a role for high fructose intake in the progression of CKD. Rats given a diet rich in fructose developed tubulointerstitial lesions and fibrosis.1 In parallel, epithelial expression of vimentin, collagen III deposition, and immune cell infiltration are increased in kidney tissues.1 After 5/6 nephrectomy, rats receiving a high-fructose diet have higher proteinuria and lower eGFR than those having dextrose-enriched or normal diet.2 Moreover, kidneys from rats with diet enriched in fructose have more severe glomerulosclerosis, tubular atrophy, and cellular infiltration.2 Finally, cultured proximal tubules cells exposed to fructose were found to release inflammatory cytokines.3 These experimental results are accompanied by consistent clinical data. Indeed, several clinical studies have shown an association of fructose intake with kidney disease, including a recently published prospective study including 3003 participants over a median follow-up of 8 years reported that higher consumption of sugar-sweetened beverages was associated with greater incidence of CKD.4 All these data suggest that high fructose intake is associated with progression of kidney disease. Strong evidence also demonstrates that endogenous fructose metabolism is involved in progressive kidney injury. Reabsorption of fructose occurs in the proximal tubule as a substrate for gluconeogenesis. Otherwise, the polyol pathway, in which glucose is converted to sorbitol by aldose reductase, is activated in patients with diabetes (Figure 1). Other conditions including renal hypoxia, high salt intake, and aging also activate the polyol pathway.Figure 1: Different mechanisms supporting the effects of fructose on CKD. Different conditions including diabetes, renal hypoxia, high salt intake, and aging activate the polyol pathway. In the proximal tubule, glucose, not used for energy, will enter in the polyol pathway and be transformed in sorbitol that can be converted to fructose, which is then largely metabolized by fructokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. AR, aldose reductase; IMP, inosine monophosphate; NO, nitric oxide; ROS, reactive oxygen species; SDH, sorbitol dehydrogenase. Figure 1 can be viewed in color online at www.cjasn.org.In the proximal tubule, glucose, not used for energy, will enter in the polyol pathway and be transformed in sorbitol that can be converted to fructose, which is then largely metabolized by fructokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. Animal models confirm the relevance of this pathway in kidney damage progression. Wild-type mice with streptozocin-induced diabetes developed proteinuria, renal insufficiency, and proximal tubular injury.5 By contrast, diabetic fructokinase-deficient mice had significantly reduced renal injuries.5 Such conditions associated with blunted fructose metabolism are inherent to CKD. Hypoxia is a hallmark of kidney injury and a pathway for progression toward end-stage renal disease. Patients with diabetic nephropathy are likely to have activation of endogenous fructose metabolism. Indeed, both renal ischemia and high glucose concentration are potent activators of the polyol pathway. Moreover, fructokinase is present in the proximal tubules. Recently, the role of endogenous fructose production in proximal tubular cells has been evoked to play a role in the pathogenesis of Mesoamerican nephropathy.6 This CKD is characterized by exposure to extreme heat and recurrent dehydration episodes. In these conditions, increased plasma osmolality may induce the activation of the polyol pathway and cause inflammation and tubular injury.6 Finally, recent experimental data strongly suggest that fructose metabolism is a key pathway in ischemic AKI (iAKI). García-Arroyo et al.7 showed that sweetened beverages hydration in rats induces mild renal alterations that are significantly worsened after ischemic injury compared with controls. Similar results were observed in humans. Stage 1 AKI occurred in 75% of young healthy adults subjected to physical exercise with high fructose hydration while stage 1 AKI occurred in only 8% with similar exercise and water hydration.8 Most convincing data result from inhibition of fructokinase in the setting of iAKI. Andres-Hernando et al.5 reported that mice undergoing iAKI had significant polyol pathway activation, whereas wild-type animals developed severe AKI, and fructokinase knock-out mice had reduced renal injury. Therefore, a very exciting strategy would be to inhibit fructokinase to prevent or reduce kidney injury. Ketohexokinase C is the C isoform of the fructokinase. Luteolin, a fructokinase inhibitor, mitigated the effects of ischemia of renal injury.5 Mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol, and endogenous fructose. Both the renal injury and dysfunction decreased when animals were exposed to luteolin.5 Osthole, a coumarinic derivative, has been proven to have inhibitory activity against ketohexokinase C. Treatment with osthole prevents the development of metabolic syndrome and ameliorates kidney damage in various models.9 Osthole ameliorates unilateral ureteral obstruction-induced renal pathological damage and renal fibrosis in vivo.10 Exposure of mice to osthole results in significantly increased urinary fructose excretion compared with vehicle-treated animals, consistent with blocking fructose metabolism. These drugs are not labeled for use in humans, but their effects in animal models are consistent with the role of fructose in different settings of kidney injury. However, some clinical data still exist with another drug. PF-06835919, also known as MDK1846, is a recently developed ketohexokinase inhibitor with an ongoing clinical development.11 Compared with placebo, PF-06835919 reduced whole liver fat in patients with nonalcoholic fatty liver disease.11 The drug was generally safe and well tolerated.11 There are currently no studies to prevent CKD with PF-06835919 in humans. However, existent preclinical and clinical data highly suggest that a strategy based on fructokinase inhibition may mitigate the development of iAKI and reduce the progression of CKD. This opens the prospect of strengthening means of preventing kidney diseases. Fructose may alter renal function and structure through different pathways and favor the progression of CKD independent of its cause. Further studies should examine whether specific dietary approaches may reduce CKD onset and progression. Furthermore, drugs targeting the polyol pathway could also prevent iAKI and mitigate the progression of CKD.