Open AccessStructure-Based Optimization of Small Molecule Human Galactokinase Inhibitors
Author(s) -
Li Liu,
Manshu Tang,
Rajan Pragani,
Frank G. Whitby,
Yaqin Zhang,
Bijina Balakrishnan,
Yuhong Fang,
Karavadhi Surendra,
Dingyin Tao,
Christopher A. LeClair,
Matthew D. Hall,
Juan Marugán,
Matthew B. Boxer,
Min Shen,
Christopher P. Hill,
Kent Lai,
Samarjit Patnaik
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00945
Subject(s) - galactosemia , galactokinase , chemistry , galactose , biochemistry , enzyme , escherichia coli , gene
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 (IC 50 < 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.