Innovative therapy for Classic Galactosemia - tale of two HTS

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Classic Galactosemia is an autosomal recessive disorder stemming from deficient galactose-1-phosphate uridylyltransferase (GALT).
• Newborn screening and dietary galactose restriction have improved neonatal outcomes, but long-term complications persist.
• Galactose-1-phosphate (gal-1P) accumulation is identified as a primary pathogenic factor in Classic Galactosemia.

Purpose of the Study:

• To review efforts in identifying therapeutic small molecule inhibitors of galactokinase (GALK).
• To explore the potential of GALK inhibition as a strategy to prevent gal-1P accumulation.
• To discuss findings from high-throughput screening and subsequent optimization of GALK inhibitors.

Main Methods:

• Experimental and computational high-throughput screening of compound libraries to identify GALK inhibitors.
• Characterization, prioritization, and optimization of identified positive compounds.
• Assessment of cross-inhibition profiles of identified GALK inhibitors against other kinases.

Main Results:

• Multiple GALK inhibitors have been identified through high-throughput screening.
• Optimization studies are underway to enhance the potency of promising compounds.
• Some identified inhibitors exhibit cross-inhibition within the GHMP small molecule kinase superfamily, distinct from glucokinase and hexokinase.

Conclusions:

• GALK inhibition presents a promising therapeutic avenue for Classic Galactosemia by targeting gal-1P accumulation.
• Further development of GALK inhibitors is crucial for improving long-term patient outcomes.
• Observed cross-inhibition may present challenges but also opens avenues for novel antimicrobial and anti-cancer therapies.