jm9b01851_si_001.pdf (12.16 MB)
Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase
journal contribution
posted on 2020-03-23, 12:35 authored by Buyun Tang, Mykhaylo S. Frasinyuk, Vimbai M. Chikwana, Krishna K. Mahalingan, Cynthia A. Morgan, Dyann M. Segvich, Svitlana P. Bondarenko, Galyna P. Mrug, Przemyslaw Wyrebek, David S. Watt, Anna A. DePaoli-Roach, Peter J. Roach, Thomas D. HurleyThe
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 efforts targeting GS activity in GSDs associated
with excess glycogen accumulation.