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Structure-activity analysis and cell-based optimization of human galactokinase inhibitors
Si Odejinmi1, Rg Rascon, M Tang
1Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, U.S.A.
ACS Medicinal Chemistry Letters
|November 30, 2011
Summary
Researchers identified small molecule GALK inhibitors to treat Classic Galactosemia by reducing toxic galactose-1-phosphate accumulation. This discovery offers a potential therapeutic strategy for this rare genetic disorder.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Classic Galactosemia is a rare genetic disorder.
- It is characterized by the accumulation of toxic levels of galactose-1-phosphate (gal-1P).
- This accumulation is caused by a deficiency in galactose-1-phosphate uridyltransferase (GALT) activity.
Purpose of the Study:
- To identify small molecule inhibitors targeting GALK.
- To reduce the toxic accumulation of gal-1P in patients with Classic Galactosemia.
- To optimize lead compounds for improved potency and efficacy.
Main Methods:
- High-throughput screening to identify over 200 GALK inhibitors.
- Selection of a 4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile scaffold.
- Structure-activity relationship characterization and lead optimization using patient cells.
Main Results:
- Identification of over 200 small molecule GALK inhibitors.
- Selection and optimization of a promising chemical scaffold.
- Demonstrated reduction of gal-1P accumulation in patient cells.
Conclusions:
- Small molecule GALK inhibitors represent a potential therapeutic approach for Classic Galactosemia.
- The identified scaffold shows promise for further development.
- Targeting GALK offers a viable strategy to mitigate gal-1P toxicity.
