Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders

Sci Transl Med. 2024 Jan 17;16(730):eadf1691. doi: 10.1126/scitranslmed.adf1691.

Julie C Ullman ¹, Kevin T Mellem ¹, Yannan Xi ¹, Vyas Ramanan ¹, Hanne Merritt ¹, Rebeca Choy ¹, Tarunmeet Gujral ¹, Lyndsay E A Young ² ³, Kerrigan Blake ¹, Samnang Tep ¹, Julian R Homburger ¹, Adam O'Regan ¹, Sandya Ganesh ¹, Perryn Wong ¹, Terrence F Satterfield ¹, Baiwei Lin ¹, Eva Situ ¹, Cecile Yu ¹, Bryan Espanol ¹, Richa Sarwaikar ¹, Nathan Fastman ¹, Christos Tzitzilonis ¹, Patrick Lee ¹, Daniel Reiton ¹, Vivian Morton ¹, Pam Santiago ¹, Walter Won ¹, Hannah Powers ¹, Beryl B Cummings ¹, Maarten Hoek ¹, Robert R Graham ¹, Sanjay J Chandriani ¹, Russell Bainer ¹, Anna A DePaoli-Roach ⁴, Peter J Roach ⁴, Thomas D Hurley ⁴, Ramon C Sun ⁵ ⁶, Matthew S Gentry ⁵, Christopher Sinz ¹, Ryan A Dick ¹, Sarah B Noonberg ¹, David T Beattie ¹, David J Morgans Jr ¹, Eric M Green ¹

Affiliations

1 Maze Therapeutics, South San Francisco, CA 94080, USA.
2 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA.
3 Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5 Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
6 USA Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL 32610, USA.

PMID: 38232139 DOI: 10.1126/scitranslmed.adf1691

Abstract

Glycogen synthase 1 (GYS1), the rate-limiting Enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this Enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α Glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-157646

MZ-101

98.98%, GYS1 Inhibitor

Others

Metabolic Disease

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