98554-01-9Relevant articles and documents
Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors
Liu, Li,Tang, Manshu,Pragani, Rajan,Whitby, Frank G.,Zhang, Ya-Qin,Balakrishnan, Bijina,Fang, Yuhong,Karavadhi, Surendra,Tao, Dingyin,LeClair, Christopher A.,Hall, Matthew D.,Marugan, Juan J.,Boxer, Matthew,Shen, Min,Hill, Christopher P.,Lai, Kent,Patnaik, Samarjit
, p. 13551 - 13571 (2021/09/28)
Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC50 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.
