Inhibition of ketohexokinase (KHK, fructokinase) may ameliorate non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) by decreasing fructose conversion to fructose-1-phosphate. Initial low-molecular weight hits were identified by fragment screening; subsequent file-mining provided multiple starting points for hit-to-lead chemistry. A combination of parallel synthesis and structure-based drug design yielded an in vivo tool compound that recapitulated the efficacy reported in a KHK-null rodent model on a high-fructose diet. Further optimization provided the clinical candidate, currently in clinical trials. This fragment-to-candidate story will present the fragment-based screen triage, compound optimization via structure-based drug design and parallel chemistry, in vivo target validation, clinical candidate selection and initial clinical data.

Discovery of a ketohexokinase inhibitor for the treatment of NAFLD/NASH: Fragment-to-candidate via structure-based drug design and parallel chemistry

254th National Meeting (2017)

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