Target Validation Information | |||||
---|---|---|---|---|---|
Target ID | T21678 | ||||
Target Name | Alpha-galactosidase A | ||||
Target Type | Clinical Trial |
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Drug Potency against Target | Beta-1-C-butenyl-1-deoxygalactonojirimycin | Drug Info | IC50 = 2000 nM | [530905] | |
(+)-5-deoxyadeenophorine | Drug Info | IC50 = 6400 nM | [528124] | ||
Beta-1-C-Butyl-1-deoxygalactonojirimycin | Drug Info | IC50 = 1200 nM | [530905] | ||
1-deoxygalactonojirimycin | Drug Info | IC50 = 3 nM | [530905] | ||
Migalastat | Drug Info | Ki = 3 nM | [552906] | ||
2,5-dideoxy-2,5-imino-D-altritol | Drug Info | IC50 = 780 nM | [530905] | ||
Action against Disease Model | AT1001 | Bottom panel. The average potency of AT1001 for mediating an increase in GLA activity for each cell line is shown. Potency is expressed as the negative log of the concentration at which 50% of the maxim uM effect is achieved (EC50). The dotted line represents the potency of the wild type control (-log[EC50] = 6.1 or 760 nM). | Drug Info | ||
The Effect of Target Knockout, Knockdown or Genetic Variations | Fabry disease is a rare X-linked disorder caused by mutations in the alpha-galactosidase gene (GLA), the resultant deficiency of lysosomal alpha-galactosidase enzyme activity leading to systemic acc uMulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifestprogressive chronic kidney disease (CKD), their relevance as a model for h uMan Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related acc uMulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in h uMans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy. | ||||
References | |||||
Ref 530905 | Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. Epub 2010 Apr 21.2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease. | ||||
Ref 528124 | Bioorg Med Chem Lett. 2006 Jun 15;16(12):3262-7. Epub 2006 Apr 5.Flexible synthesis and biological evaluation of novel 5-deoxyadenophorine analogues. | ||||
Ref 530905 | Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. Epub 2010 Apr 21.2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease. | ||||
Ref 530905 | Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. Epub 2010 Apr 21.2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease. | ||||
Ref 552906 | Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther. 2009 Mar;328(3):723-31. doi: 10.1124/jpet.108.149054. Epub 2008 Dec 23. | ||||
Ref 530905 | Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. Epub 2010 Apr 21.2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease. |
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