Kevin T. Mellem

Bioluminescent Assay for the Quantification of Cellular Glycogen Levels

Donna Leippe, Rebeca Choy, Gediminas Vidugiris, Hanne Merritt et autres

Glycogen is a large polymer of glucose that functions as an important means of storing energy and maintaining glucose homeostasis. Glycogen synthesis and degradation pathways are highly regulated and their dysregulation can contribute to disease. Glycogen storage diseases are a set of …

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A Bioluminescent Assay for Quantification of Cellular Glycogen Levels

Donna Leippe, Rebeca Choy, Gediminis Vidugiris, Hanne Merritt et autres

Glycogen is a large polymer of glucose that functions as an important means of storing energy and maintaining glucose homeostasis. Glycogen synthesis and degradation pathways are highly regulated and their dysregulation can contribute to disease. Glycogen storage diseases are a set of …

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

Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Vyas Ramanan et autres

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 …

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Small molecule inhibition of glycogen synthase 1 restores autophagolysosomal and metabolic pathway dysfunction in a mouse model of Pompe disease

Julie C. Ullman, Yannan Xi, Kevin T. Mellem, Hanne Merritt et autres

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

G. Leslie Burnett, Yu Chi Yang, James B. Aggen, Jennifer Pitzen et autres

High Resolution Image Download MS PowerPoint Slide Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual …

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The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex

Nathan M. Fastman, Yuxi Liu, Vyas Ramanan, Hanne Merritt et autres

Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by autoglucosylation, and glycogen synthase-1 (GYS1), which …

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In-vitro characterization of MZE001, an orally active GYS1 inhibitor to treat Pompe disease

Rebeca Choy, Daniel Reiton, Hanne Merritt, Tarunmeet Gujral et autres

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Substrate reduction therapy for Pompe disease: Small molecule inhibition of glycogen synthase 1 in preclinical models

Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Terrence F. Satterfield et autres

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Pharmacology of small molecule inhibitors of GYS1 in a mouse model of Pompe disease

Yannan Xi, Terrence F. Satterfield, Rebeca Choy, Tarunmeet Gujral et autres

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Abstract 4877: Allosteric inhibition of SHP2 variants containing cancer-associated activating mutations

David Wildes, Naing Aay, Andreas Buckl, Daphne Hsieh et autres

Abstract SHP2 (PTPN11) is a non-receptor protein tyrosine phosphatase and scaffold protein that functions in multiple signal transduction pathways. Genetic and pharmacologic evidence supports a role for SHP2 in driving the proliferation of cancer cells dependent upon a range of activated RTKs, …

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Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity

Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar et autres

Abstract Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS …

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On the Development of Pseudoephenamine and Its Applications in Asymmetric Synthesis

Kevin T. Mellem

Pseudoephedrine is well established as a chiral auxiliary in the alkylation of amide enolates to form tertiary and quaternary carbon stereocenters. However, due to its facile transformation into the illegal narcotic methamphetamine, pseudoephedrine is either illegal or highly regulated in many countries, …