MK-8719 / Alectos, Merck (MSD) - LARVOL DELTA

Identification of HK3 as a Potential Key Biomarker in the Progression of Temporomandibular Joint Osteoarthritis via RNA Sequencing. (PubMed, Biology (Basel)) - "Three drugs (MK8719, LY3372689, and Thiamet-G) targeting HK3 were identified through the Drug-Gene Interaction Database (DGIdb) screening, and molecular docking demonstrated high binding affinity between these drugs and HK3. This study suggests that HK3 may play a role in TMJOA progression and could serve as a potential biomarker for inflammatory progression in TMJOA. Targeting HK3 may offer new diagnostic and therapeutic strategies for TMJOA management."

Biomarker • Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Regulation of Metabolic Homeostasis By TRAF6 Contributes to the Leukemia Progression (ASH 2023) - "The treatment with MK8719 (OGA inhibitor) mildly, but significantly, restored the number of TRAF6 knockdown AML cells, which was correlated with the changes in mitochondrial function, indicating that O-GlcNAc modification regulated by TRAF6 is important for AML progression. In summary, We provide evidence for the oncogenic function of TRAF6 in leukemia, and shed light on the novel TRAF6/OGT/O-GlcNAc axis that regulates the metabolic reprogramming required for leukemogenesis."

IO biomarker • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • OGA • OGT • TRAF6

Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat. (PubMed, bioRxiv) - "Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions."

Journal • Alzheimer's Disease • CNS Disorders • Depression • Psychiatry • OGA • SYP

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. (PubMed, J Pharmacol Exp Ther) - "In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of AD and other tauopathies."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Discovery of MK-8719, A Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. (PubMed, J Med Chem) - "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) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human Phase I clinical trials."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Sugar Kick Prevents Memory Impairment. (PubMed, J Med Chem) - "A recent study showed that MK-8719 (6) is a selective and potent small molecule inhibitor of human O-GlcNAcase (hOGA). The OGA inhibitor slows neurodegeneration and improves cognitive function in AD and related tauopathies. Here, we discuss the findings of that study and the development of OGA inhibitors as novel therapeutic strategy for treatment of age-related memory impairment in neurodegenerative diseases."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Discovery of MK-8719: Potent O-GlcNAcase inhibitor as a potential treatment for tauopathies (ACS-Fall 2019) - "Consistent with this idea, multiple independent studies using transgenic murine models of tauopathy have shown that administration of the small-molecule OGA inhibitor Thiamet-G confers beneficial effects, including: reduced phosphorylated tau species and tau aggregates, reduced tau levels in cerebrospinal fluid, decreased neuronal cell loss, and reduced disease-associated behavioral phenotypes. On the basis of these findings, OGA inhibition has emerged as a therapeutic strategy to treat tau pathology in AD and other tauopathies."