Author: Hill, Christopher P. ; Liu, Li ; Hall, Matthew D. ; Marugan, Juan J. ; Tao, Dingyin ; Whitby, Frank G. ; Shen, Min ; Fang, Yuhong ; Lai, Kent ; LeClair, Christopher A. ; Patnaik, Samarjit ; Tang, Manshu ; Karavadhi, Surendra ; Balakrishnan, Bijina ; Pragani, Rajan ; Zhang, Ya-qin ; Boxer, Matthew

Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC₅₀ < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.

01 Feb 2015·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Structure activity relationships of human galactokinase inhibitors

Q4 · MEDICINE

Article

Author: Lai, Kent ; Rohde, Jason M ; Liu, Li ; Tanega, Cordelle ; Baker, Heather L ; Shen, Min ; Pragani, Rajan ; Leister, William H ; Walsh, Martin J ; Blackman, Burchelle ; Bougie, James M ; Tang, Manshu ; Brimacombe, Kyle R ; Boxer, Matthew B ; Fernandez, Elizabeth ; Auld, Douglas S

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.

08 Sep 2011·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Structure–Activity Analysis and Cell-Based Optimization of Human Galactokinase Inhibitors

Q3 · MEDICINE

Article

Author: Lai, Kent ; Rascon, Rafael G. ; Odejinmi, Sina I. ; Vankayalapati, Hariprasad ; Tang, Manshu

Classic Galactosemia is a rare human disease associated with the accumulation of toxic level of galactose-1-phosphate (gal-1P) caused by the inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) activity. To reduce the toxic level of gal-1P in the patients, we have identified, via high-throughput screening, over 200 small molecule GALK inhibitors. We selected a 4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile scaffold for further structure-activity relationships characterization, lead optimization with regards to potency and efficacy to reduce gal-1P accumulation in patient cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Galactosemias	Discovery	United States	National Institutes of Health	-

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