2. Academic Validation
  3. Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors

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

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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