Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors

  • J Med Chem. 2021 Sep 23;64(18):13551-13571. doi: 10.1021/acs.jmedchem.1c00945.
Li Liu  1 ,  Manshu Tang  2 ,  Rajan Pragani  1 ,  Frank G Whitby  3 ,  Ya-Qin Zhang  1 ,  Bijina Balakrishnan  2 ,  Yuhong Fang  1 ,  Surendra Karavadhi  1 ,  Dingyin Tao  1 ,  Christopher A LeClair  1 ,  Matthew D Hall  1 ,  Juan J Marugan  1 ,  Matthew Boxer  1 ,  Min Shen  1 ,  Christopher P Hill  3 ,  Kent Lai  2 ,  Samarjit Patnaik  1
Affiliations
  • 1. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 2. Department of Pediatrics, University of Utah, Salt Lake City, Utah 84108-6500, United States.
  • 3. Department of Biochemistry, University of Utah School of Medicine, 15 North Medical Drive East, Salt Lake City, Utah 84112, United States.
PMID: 34491744 DOI: 10.1021/acs.jmedchem.1c00945
Abstract

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.

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