title: Structure activity relationships of human galactokinase inhibitors.
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.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Rm 2C412 SOM, 50 N. Medical Drive, Salt Lake City, UT 84132, USA.
authors.forename: Manshu
authors.initials: M
authors.lastname: Tang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Pragani
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Cordelle
authors.initials: C
authors.lastname: Tanega
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Rohde
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Baker
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Burchelle
authors.initials: B
authors.lastname: Blackman
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Bougie
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Leister
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Rm 2C412 SOM, 50 N. Medical Drive, Salt Lake City, UT 84132, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Lai
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA. Electronic address: boxerm@mail.nih.gov.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005686:Galactokinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005695:Galactosephosphates / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D005695:Galactosephosphates; D011994:Recombinant Proteins; D013141:Spiro Compounds; C029973:galactose-1-phosphate; D005686:Galactokinase
keywords: Galactokinase; Galactosemia; Structure–activity relationships