Development landscape of ketohexokinase-C (KHK-C) inhibitors for fructose-driven metabolic disorders: from hit discovery to clinical trials.

Ketohexokinase (KHK) aka fructokinase, initiates fructose metabolism by catalyzing the ATP-dependent phosphorylation of fructose. Unlike glucose metabolism, which is stringently regulated by numerous hormonal and allosteric mechanisms, fructose metabolism largely bypasses these checkpoints. This is primarily because KHK, unlike glucokinase, is not subject to significant allosteric regulation, resulting in rapid and uncontrolled fructose metabolism. This rapid flux of fructose through the KHK-mediated fructolysis pathway drives the pathogenesis of metabolic dysfunction-associated liver diseases (NAFLD and NASH), obesity, and type 2 diabetes. Moreover, the global consumption of fructose-rich sweeteners and processed foods has increased substantially over the past several decades, amplifying the burden of fructose-driven metabolic disorders (FDMDs). Consequently, KHK has emerged as a promising therapeutic target for the treatment of FDMDs. Genetic deletion and knockdown studies have demonstrated that the suppression of KHK activity protects against FDMDs. Furthermore, pharmacological inhibition of KHK has shown promising efficacy in preclinical and clinical studies, with several candidates demonstrating improvements in the metabolic profile of patients with FDMDs. This review provides an overview of the biological function of KHK in fructose metabolism and its involvement in metabolic diseases. It also discusses the structure and catalytic mechanism of KHK and provides a detailed overview of KHK inhibitor discovery and development, from initial hit identification and lead optimization to preclinical development and clinical evaluation.