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Bioorg Med Chem Lett. 2015 Feb 1;25(3):721-7. doi: 10.1016/j.bmcl.2014.11.061. Epub 2014 Dec 13.

Structure activity relationships of human galactokinase inhibitors.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
2
Division of Medical Genetics, Department of Pediatrics, University of Utah, Rm 2C412 SOM, 50 N. Medical Drive, Salt Lake City, UT 84132, USA.
3
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA. Electronic address: boxerm@mail.nih.gov.

Abstract

Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor.

KEYWORDS:

Galactokinase; Galactosemia; Structure–activity relationships

PMID:
25553891
DOI:
10.1016/j.bmcl.2014.11.061
[Indexed for MEDLINE]

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