Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase.

Journal of Medicinal Chemistry
Buyun TangT D Hurley

Abstract

The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development effort...Continue Reading

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Citations

Oct 10, 2020·Annals of Clinical and Translational Neurology·Erin E ChownBerge A Minassian
Aug 21, 2020·The Journal of Biological Chemistry·Silvia NitschkeFelix Nitschke
Dec 6, 2020·The Journal of Biological Chemistry·Silvia NitschkeBerge A Minassian
Apr 9, 2021·Clinical Biochemistry·Zoe R SimmonsMatthew S Gentry
May 5, 2021·Epilepsy & Behavior : E&B·Kia H MarkussenMatthew S Gentry
Jul 25, 2021·Revue neurologique·S MitraB A Minassian
Aug 18, 2021·Orphanet Journal of Rare Diseases·Federica PondrelliFrancesca Bisulli
Sep 29, 2021·Chemical Society Reviews·Louise J WalportJoel P Mackay
Nov 11, 2021·IScience·M Kathryn BrewerMatthew S Gentry

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