A5026565632- Lysosomal Storage Disorders Research
- Carbohydrate Chemistry and Synthesis
- Glycogen Storage Diseases and Myoclonus
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Asymmetric Hydrogenation and Catalysis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Advanced Synthetic Organic Chemistry
- Protein Tyrosine Phosphatases
- Analytical Chemistry and Chromatography
- Galectins and Cancer Biology
- Genetics and Neurodevelopmental Disorders
- bioluminescence and chemiluminescence research
- RNA modifications and cancer
- Crystallography and molecular interactions
- PI3K/AKT/mTOR signaling in cancer
- Lanthanide and Transition Metal Complexes
- Luminescence Properties of Advanced Materials
- Pineapple and bromelain studies
- Cancer, Hypoxia, and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Ionic liquids properties and applications
- Melanoma and MAPK Pathways
Maze (United States)
2022-2024
Revolution Medicines (United States)
2018-2022
Harvard University
2012-2013
University of South Dakota
2007
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role energy homeostasis and has been proposed as therapeutic target multiple storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors this enzyme. Here, we report preclinical characterization MZ-101, small molecule that potently inhibits GYS1 vitro vivo without inhibiting GYS2, related isoform essential for synthesizing liver glycogen....
Unrestricted: Pseudoephenamine is introduced as a versatile chiral auxiliary and an alternative to pseudoephedrine in asymmetric synthesis. It free from regulatory restrictions leads remarkable stereocontrol alkylation reactions, especially those that form quaternary carbon centers. Amides derived pseudoephenamine exhibit high propensity be crystalline substances, provide sharp, well-defined signals NMR spectra.
Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or crosstalk with other mutant cancer drivers, such as RAS, is a feature many tumors. Multiple allosteric inhibitors mTORC1 and orthosteric dual mTORC2 have been developed anticancer drugs, but their clinical utility has limited. To address these limitations, we novel class "bi-steric inhibitors" that interact both binding sites order to deepen inhibition while also preserving selectivity for over mTORC2. In this report,...
Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result storage diseases (GSDs). In muscle, synthesis initiated by enzymes glycogenin-1 (GYG1), which seeds molecule autoglucosylation, synthase-1 (GYS1), extends chain. Although both are required for proper production, nature their interaction has been enigmatic. Here, we present human GYS1:GYG1 complex multiple conformations representing different functional states. We observe an asymmetric...
The effect of relative water content on the luminescence properties and speciation Eu3+ ions in solutions EuCl3 binary solvent mixture water/[BMI]Cl is presented, where [BMI]Cl ionic liquid (IL) 1-butyl-3-methylimidazolium chloride. Using techniques, binding to are determined for samples with mole ratios water-to-IL ranging from 0 5. Very little binds at less than 1, above which increases rapidly increasing concentration. It shown that only certain hydration numbers complexes stable water/IL...
Uneingeschränkt: Pseudoephenamin wird als vielseitiges chirales Auxiliar und eine Alternative zu Pseudoephedrin in der asymmetrischen Synthese vorgestellt. Es hat keine regulatorischen Einschränkungen führt bemerkenswerter Stereokontrolle Alkylierungen, vor allem solchen, die ein quartäres Kohlenstoffzentrum aufbauen. Aus erhaltene Amide sind meist kristalline Substanzen ergeben scharfe, gut definierte Signale ihren NMR-Spektren.
The utility of pseudoephenamine as a chiral auxiliary for the alkylative construction quaternary α-methyl α-amino acids is demonstrated. method notable high diastereoselectivities alkylation reactions, its versatility with respect to electrophilic substrate partners, and mild hydrolysis conditions, which provide without salt contaminants. Alternatively, esters can be obtained by direct alcoholysis.
A three-step synthesis of pseudoephenamine suitable for preparing multigram amounts both enantiomers the auxiliary from inexpensive starting material benzil is described. The sequence involves crystalline monomethylimine derivative benzil, reduction that substance with lithium aluminum hydride, and resolution mandelic acid.
Abstract Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) scaffold encoded by the PTPN11 gene, is convergent signal transduction node integrates growth factor signals from multiple receptors to promote activation of RAS its downstream effectors. Guided structural insights X-ray data, we describe strategy aimed at identification highly potent selective allosteric SHP2 inhibitor series. Our efforts led discovery RMC-4550, which exhibits...
Glycogen is a large polymer of glucose that functions as an important means storing energy and maintaining homeostasis. synthesis degradation pathways are highly regulated their dysregulation can contribute to disease. storage diseases set disorders arise from improper glycogen metabolism. disease II, known Pompe disease, caused by genetic mutation leads increased in cells tissues, resulting progressive muscle atrophy respiratory decline for patients. One approach treating reduce levels...
Glycogen is a large polymer of glucose that functions as an important means storing energy and maintaining homeostasis. synthesis degradation pathways are highly regulated their dysregulation can contribute to disease. storage diseases set disorders arise from improper glycogen metabolism. disease II, known Pompe disease, caused by genetic mutation leads increased in cells tissues, resulting progressive muscle atrophy respiratory decline for patients. One approach treating reduce levels...
Abstract SHP2 (PTPN11) is a non-receptor protein tyrosine phosphatase and scaffold that functions in multiple signal transduction pathways. Genetic pharmacologic evidence supports role for driving the proliferation of cancer cells dependent upon range activated RTKs, certain RAS BRAF mutations, NF1 loss-of-function mutations. In addition, dominant activating mutations PTPN11 fuel pathogenic RAS/MAPK signaling underlie human RASopathies (40% Noonan syndrome 80% LEOPARD syndrome) cancers (35%...
Abstract Pseudoephenamine (PEA) is introduced as a versatile chiral auxiliary and an alternative to pseudoephedrine in asymmetric synthesis.