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O-GlcNAcylation Regulates Dopamine Neuron Function, Survival and Degeneration in Parkinson Disease

The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic [...]

December 1st, 2020|Tags: , , |

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy [...]

July 1st, 2020|Tags: , , , , , , |

Discovery of MK-8719, A Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) [...]

September 10th, 2019|Tags: , , , , , |

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: , , , |

Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, [...]

June 1st, 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: , , , , , , |

Alectos Supports NSERC Funding for Prof. A.J. Bennet at SFU

Feb 11, 2016 – Alectos today announced its support for NSERC funding for the group of Prof. A.J. Bennet at Simon Fraser University, Department of Chemistry, in a project titled “Fundamental Studies on the Biochemical Mechanism of Chemical Chaperoning of Glucocerebrosidase”. Parkinson's disease is a worldwide health problem that has been linked to deficiencies in [...]

February 11th, 2016|Tags: , , , , |

Alectos Engages As Industry Partner in the Canadian Glycomics Network (GlycoNet)

Feb 17, 2015 – Alectos today announced its support as an industry partner in the new Canadian Glycomics Network (GlycoNet), unveiled this month by Minister of Health Rona Ambrose with a commitment of $27.3 million in federal funding over five years. GlycoNet’s vision is to link academic, government and industry partners to deliver solutions to [...]

February 17th, 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: , , , |