OGA

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The Discovery and Characterization of [18F]MK‐8553, a Novel PET Tracer for Imaging O‐GlcNAcase (OGA)

[18F]MK-8553 is a high affinity, selective OGA inhibitor with properties suitable for imaging OGA and determining central enzyme occupancy in both preclinical and clinical studies. Currently [18F]MK‐8553 is being utilized in humans as a PET tracer to assess CNS target engagement to select a dose for clinical proof of concept trials with a small molecule [...]

July 14th, 2016|Tags: , , , |

Alectos Therapeutics Announces FDA Orphan Drug Designation for MK-8719: An Investigational Small-molecule OGA Inhibitor for Treatment of Progressive Supranuclear Palsy

Advances Novel Tau-directed Strategy for Treating Neurodegenerative Disease Phase 1 Clinical Trial Completed Vancouver, British Columbia (April 20, 2016) – Alectos Therapeutics Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OGA inhibitor MK-8719 for the treatment of progressive supranuclear palsy (PSP). Alectos also announced completion of [...]

April 20th, 2016|Tags: , , , , , |

Preclinical Data Disclosed for Tau PET Tracer MK-6240: A Potential Clinical Biomarker for OGA Inhibitor MK-8719

Apr 18, 2016 – Alectos Therapeutics partner Merck, known as MSD outside the U.S. and Canada, today disclosed preclinical data for potential clinical biomarker [18F]-MK-6240, a highly selective and specific tau PET tracer useful as an imaging agent for quantification of neurofibrillary tangles (NFTs). A pathological hallmark of Alzheimer's disease, as well as several other neurodegenerative [...]

April 18th, 2016|Tags: , , , , , , |

Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase

The modification of nucleocytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) plays diverse roles in multicellular organisms. Inhibitors of O-GlcNAc hydrolase (OGA), the enzyme that removes O-GlcNAc from proteins, lead to increased O-GlcNAc levels in cells and are seeing widespread adoption in the field as a research tool used in cells and in vivo. Here we synthesize [...]

February 15th, 2016|Tags: , , |

O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson’s disease

Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein [...]

October 12th, 2015|Tags: , , |

Alectos Therapeutics Announces Achievement of Phase I Clinical Milestone in Merck Alzheimer’s Collaboration

Vancouver, British Columbia (December 12, 2014) – Alectos Therapeutics Inc. today announced the initiation of a Phase I clinical trial in its collaboration with Merck, known as MSD outside the U.S. and Canada, to identify and develop compounds that modulate O-linked N-acetylglucosaminidase (OGA), an enzyme that is believed to be involved in the development of [...]

December 12th, 2014|Tags: , , , |

Alectos Announces Preclinical Results in TAPP Mouse Model of Alzheimer’s Disease

Oct 26, 2014 – Alectos today announced publication of preclinical studies showing that pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in the TAPP mouse model of Alzheimer’s disease. For details, see: Yuzwa, S.A. et al. Mol Neurodegener 9:42 (2014).

October 26th, 2014|Tags: , , , , , , , |

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of [...]

October 26th, 2014|Tags: , , , , , , , |

The emerging link between O-GlcNAc and Alzheimer disease

Regional glucose hypometabolism is a defining feature of Alzheimer disease (AD). One emerging link between glucose hypometabolism and progression of AD is the nutrient-responsive post-translational O-GlcNAcylation of nucleocytoplasmic proteins. O-GlcNAc is abundant in neurons and occurs on both tau and amyloid precursor protein. Increased brain O-GlcNAcylation protects against tau and amyloid-β peptide toxicity. Decreased O-GlcNAcylation [...]

October 21st, 2014|Tags: , , , , , , , , , , |

Chronic O-β-N-acetylglucosaminylase inhibition with Thiamet-G prevents tau pathology and hyperactivity in rTg4510 mice

Background: The abnormal hyperphosphorylation of the microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD) and aggregation of hyperphosphorylated tau into neurofibrillary tangles is a hallmark brain lesion in AD. Besides kinases and phosphatases tau phosphorylation is regulated by O-GlcNAcylation, a posttranslational modification of proteins on the serine or threonine residues with [...]

September 6th, 2014|Tags: , , , , , |