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Structure activity relationships of human galactokinase inhibitors

Liu, L, Tang, M, Walsh, MJ, Brimacombe, KR, Pragani, R, Tanega, C, Rohde, JM, Baker, HL, Fernandez, E, Blackman, B, Bougie, JM, Leister, WH, Auld, DS, Shen, M, Lai, K and Boxer, MB (2015) Structure activity relationships of human galactokinase inhibitors. Bioorganic and Medicinal Chemistry Letters. pp. 721-727.


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

Item Type: Article
Additional Information: NIBR author: Auld, DS institute: NIBR-address only contributor address: (Liu, Walsh, Brimacombe, Pragani, Tanega, Rohde, Baker, Fernandez, Blackman, Bougie, Leister, Auld, Shen, Boxer) National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States (Tang, Lai) Division of Medical Genetics, Department of Pediatrics, University of Utah, 50 N. Medical Drive, Salt Lake City, UT 84132, United States (Walsh) Dow AgroSciences LLC, Crop-Protection Discovery, Group, Bldg. 306/E2/980, 9330 Zionsville Road, Indianapolis, IN 46268, United States (Blackman) Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States (Auld) Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, United States
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11


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