biostudies-literatureUllman JCNIDDK NIH HHSNINDS NIH HHSeadf1691https://www.ebi.ac.uk/biostudies/studies/S-EPMC10962247biostudies-literatureUnknown16(730)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 abnScience translational medicineSmall-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.PMC10962247R35 NS116824R01 DK027221DePaoli-Roach AALee PMorgans DJRamanan VSarwaikar RBeattie DTCummings BBGreen EMPowers HHoek MNoonberg SBBlake KGanesh SWon WHurley TDEspanol BYoung LEAO'Regan ABainer RFastman NDick RAMerritt HSun RCSantiago PXi YChoy RHomburger JRWong PChandriani SJTzitzilonis CRoach PJMellem KTSatterfield TFLin BMorton VGentry MSYu CUllman JCGujral TReiton DSinz CSitu EGraham RRTep SfalseSmall-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.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 abn2024-01-01T00:00:00Z2024 Jan2026-06-01T17:53:42.437Z2025-04-06T01:15:10.978ZS-EPMC109622473823213910.1126/scitranslmed.adf1691