Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase

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. Hurley

doi:10.1021/acs.jmedchem.9b01851

Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase

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. Hurley

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43 Scopus citations

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 efforts targeting GS activity in GSDs associated with excess glycogen accumulation.

Original language	English
Pages (from-to)	3538-3551
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01851
State	Published - Apr 9 2020

Bibliographical note

Publisher Copyright:
© 2020 American Chemical Society.

Funding

The work at IUPUI was supported by NIH grants R01-DK079887 (TDH), R01-DK27221 (PJR), and P01-NS056454 (Project 3, PJR). BT was supported by the DeVault Fellowship of the Indiana University Diabetes and Obesity Program. The work at UK was supported by the Organic Synthesis Core under NIH P01 NS097197 (to M. Gentry), NIH P30 CA177558 (to L. Hersh), the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and NIH UL1 TR000117 from the National Institutes of Health for University of Kentucky’s Center for Clinical and Translational Science. The work at IUPUI was supported by NIH grants R01-DK079887 (TDH), R01-DK27221 (PJR) and P01-NS056454 (Project 3, PJR). BT was supported by the DeVault Fellowship of the Indiana University Diabetes and Obesity Program. The work at UK was supported by the Organic Synthesis Core under NIH P01 NS097197 (to M. Gentry), NIH P30 CA177558 (to L. Hersh), the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and NIH UL1 TR000117 from the National Institutes of Health for University of Kentucky's Center for Clinical and Translational Science. We would like to thank the staff at the Structural Biology Center Beamline 19-ID. Results shown in this report were derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. We also thank Dr. Lifan Zeng and Erica Woodall in the Chemical Genomics Core Facility for assistance with LC/MS. We also specifically thank Dr. Steven M. Johnson for his valuable discussions and recommendations.

Funders	Funder number
Center for Pharmaceutical Research and Innovation in the College of Pharmacy	UL1 TR000117
National Institutes of Health for University of Kentucky's Center for Clinical and Translational Science
National Institutes of Health for University of Kentucky’s Center for Clinical and Translational Science
National Institutes of Health (NIH)	P30 CA177558, R01-DK27221, P01-NS056454, P01 NS097197
U.S. Department of Energy EPSCoR
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK079887
Office of Science Programs
Biological and Environmental Research	DE-AC02-06CH11357
Argonne National Laboratory

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.9b01851

Cite this

Tang, B., Frasinyuk, M. S., Chikwana, V. M., Mahalingan, K. K., Morgan, C. A., Segvich, D. M., Bondarenko, S. P., Mrug, G. P., Wyrebek, P., Watt, D. S., Depaoli-Roach, A. A., Roach, P. J., & Hurley, T. D. (2020). Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase. Journal of Medicinal Chemistry, 63(7), 3538-3551. https://doi.org/10.1021/acs.jmedchem.9b01851

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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 {\AA}, 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.",

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AU - Mahalingan, Krishna K.

AU - Morgan, Cynthia A.

AU - Segvich, Dyann M.

AU - Bondarenko, Svitlana P.

AU - Mrug, Galyna P.

AU - Wyrebek, Przemyslaw

AU - Watt, David S.

AU - Depaoli-Roach, Anna A.

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Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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