Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Classic galactosemia is a rare genetic disorder resulting from galactose-1 phosphate uridylyltransferase (GALT) deficiency.
• Elevated galactose-1 phosphate (gal-1P) levels are implicated in the chronic complications of galactosemia, a condition lacking current treatments.
• Inhibiting galactokinase 1 (GALK1), which produces gal-1P, is a potential therapeutic strategy.

Purpose of the Study:

• To develop novel, potent inhibitors of human GALK1.
• To optimize lead compounds through structure-based drug design.
• To evaluate the efficacy of these inhibitors in cellular models of classic galactosemia.

Main Methods:

• Structure-based structure-activity relationship (SAR) optimization of a previously identified dihydropyrimidine inhibitor.
• Biochemical assays to determine inhibitor potency (IC50).
• Cell-based assays using patient-derived cells to assess gal-1P accumulation.
• Pharmacokinetic profiling in preclinical models.

Main Results:

• Novel analogs with potent biochemical inhibition of GALK1 (IC50 < 100 nM) were generated.
• Lead compounds demonstrated efficacy in preventing gal-1P accumulation in patient-derived cells at low micromolar concentrations.
• The developed compounds exhibited suitable pharmacokinetic properties for further preclinical evaluation.

Conclusions:

• Structure-based optimization yielded highly potent GALK1 inhibitors.
• These novel compounds represent a promising therapeutic avenue for classic galactosemia by targeting gal-1P accumulation.
• Further preclinical studies in rodent models are warranted to assess in vivo efficacy.