LY3522348 / Eli Lilly - LARVOL DELTA

Ketohexokinase: A Central Mediator of Fructose-Associated Pathogenesis and Promising Therapeutic Target. (PubMed, Pharmacol Res) - "Translational development of KHK inhibitors has achieved notable progress, with the first-generation PF-06835919 completing Phase 2 trials for metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and hereditary fructose intolerance, and the second-generation LY3522348 finishing Phase 1 evaluation in healthy participants, though key gaps including isoform selectivity and tissue-specific delivery remain unaddressed. Despite growing recognition of KHK's multifaceted roles in health and disease, existing literature lacks a consolidated synthesis of its regulation, tissue-specific functions, and translational progress. This review aims to provide a systematic overview of KHK's molecular characteristics, regulatory networks, pathophysiological roles, and therapeutic potential, establishing KHK as a promising actionable target for fructose-related disorders and offering a foundational framework to guide future research and drug development."

Journal • Review • Diabetes • Diabetic Nephropathy • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Obesity • Oncology • Renal Disease • Type 2 Diabetes Mellitus

LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults. (PubMed, Diabetes Ther) - P1 | "LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism. The study was registered on ClinicalTrials.gov (NCT04559568)."

Journal • P1 data • Metabolic Dysfunction-Associated Steatohepatitis

Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders. (PubMed, Front Pharmacol) - "Pfizer's PF-06835919 has progressed to phase II trials, demonstrating a reduction in liver fat and improved insulin sensitivity, while Eli Lilly's LY-3522348 also shows significant potential. ADMET profiling refined the selection to five compounds (1, 2, and 4-6), and molecular dynamics simulations identified compound 2 as the most stable and promising candidate compared to the clinical candidate PF-06835919. These findings highlight compound 2 as a potent KHK-C inhibitor with predicted pharmacokinetics and toxicity profiles supporting its potential for treating fructose-driven metabolic disorders, warranting further validation."

Journal • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology

Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach. (PubMed, Pharmaceuticals (Basel)) - " Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from -45.51 to -61.3 kcal/mol), LY-3522348 (-45.36 kcal/mol), and reported marine-derived inhibitors (from -22.74 to -51.83 kcal/mol)... Hit 8 emerged as the most promising candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven metabolic disorders, warranting further experimental validation."

Journal • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor. (PubMed, J Med Chem) - "Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials."

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