A peculiar feature common to certain rare diseases and cancers is the overaccumulation of glycogen. Glycogen Storage Diseases (GSDs) are a group of rare genetic disorders defined by an overaccumulation of glycogen in various tissues that often proves fatal. This overaccumulation can be attributed to malformed, insoluble glycogen particles or deficiencies in glycogen digesting enzymes. Knockdown of Glycogen Synthase 1 (GYS1), the rate-limiting enzyme of glycogenesis, in preclinical models of GSDs reduced pathological glycogen accumulation and has validated GYS1 as a potential therapeutic entry point for these indications. The genetic knockdown of GYS1 in certain cancer xenografts reduces tumor volume, but GYS1 as a therapeutic target in cancer, including glycogen’s role in tumorigenesis beyond an energy source, requires further investigation. Despite the significance of this metabolic pathway, there is currently no targeted, small molecule chemical probe of GYS1 to interrogate the inhibition of glycogenosis in these indications. Meanwhile, there has been a recent surge in the development of bifunctional molecules known as proteolysis-targeting chimeras (PROTACs) as therapeutics and chemical probes. Targeted protein degradation has revolutionized drug discovery and provides a new approach to drug the “undruggable”. Despite the first demonstration over twenty years ago, designing and discovering PROTACs for therapeutic targets have recently become a bona fide strategy in small-molecule drug development. Herein, this dissertation discloses efforts to discover PROTACs that induce GYS1 degradation to further examine the physiological role of glycogen and potentially add to the toolkit of therapeutics for targeted glycogen depletion.Ph.D.2025-06-26 00:00:0
