O-linked N-acetylglucosaminidase / Summit Therapeutics - LARVOL DELTA

Discovery of Sennoside A as a Natural O-GlcNAcase Inhibitor That Ameliorates Parkinson's Disease by Restoring EphrinB2 O-GlcNAcylation. (PubMed, Research (Wash D C)) - "Disruption of EphrinB2 O-GlcNAcylation by Ser40A/Thr183A mutation eliminates its neuroprotective function and abolishes the anti-PD effects of SA. Collectively, this work establishes the pharmacological inhibition of OGA as a promising therapeutic strategy for PD and identifies SA as a naturally occurring anti-PD agent that alleviates PD-associated pathological phenotypes by inhibiting OGA-mediated de-O-GlcNAcylation of EphrinB2."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • EPHB4 • OGA

Chemical biology tools for the O-GlcNAc modification: Determining systems-level functions and druggability. (PubMed, Curr Opin Chem Biol) - "Recent OGA inhibitor clinical challenges in Phase 1 and 2 studies pose existential questions about drugging O-GlcNAc, but recent advances covered in this Opinion propose insights for safe therapeutic targeting. Through the lens of new chemical biology tools, we see detailed patterns in how nutrient-responsive O-GlcNAcylation subtly regulates cellular decision-making."

Journal • Review

Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation. (PubMed, Brain Sci) - "Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Huntington's Disease • Movement Disorders • Parkinson's Disease • OGA

Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial. (PubMed, JAMA) - P2 | "Ceperognastat did not slow disease progression of early symptomatic AD. ClinicalTrials.gov Identifier: NCT05063539."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • STAT3

Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies. (PubMed, ACS Med Chem Lett) - "Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation."

Journal • Alzheimer's Disease • CNS Disorders • OGA

Cancer metabolism in radiation sensitization: complementary roles of O-GlcNAc Transferase (OGT) and PARP1. (PubMed, J Cell Sci) - "The OGA inhibitor PUGNAc suppressed hyperresection due to PARP1 knockout while PARP inhibitor veliparib exacerbated defects in OGT- or EZH2-deficient cells. Our results highlight the potential of targeting cancer-associated metabolic reprogramming to overwhelm HR repair and drive resection stress. Combining PARP inhibition with blockade of O-GlcNAcylation or EZH2 may offer a strategy to radiosensitize proliferating, HR-proficient cancers while sparing non-cycling normal tissues."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA1 • OGA • PARP1 • RAD51

Thiamet-G facilitates reparative dentin formation via modulating O-GlcNAcylation and inflammation. (PubMed, Front Physiol) - "Particularly, at 42 days, Thiamet-G treated specimens exhibited enhanced dentin-bridge formation, confirmed by micro-CT imaging and histology. Thiamet-G treatment facilitated reparative dentin formation by modulating inflammation and regulating regenerating signaling, suggesting its potential as a therapeutic agent."

Journal • Inflammation • BMP2 • NES • OGA • RUNX2 • TGFB1 • TNFA

Small molecule splicing modulators that disrupt O-GlcNAc homeostasis. (PubMed, Nat Commun) - "Here we report the results of three parallel drug repurposing screens against the O-GlcNAc cycling enzymes in cells and in vitro that reveal kinase inhibitors GSK690693 and Y-33075 act as splicing modulators that disrupt O-GlcNAc homeostasis and simultaneously downregulate OGT and OGA. Evaluation of a panel of splicing modulators revealed three additional potent compounds (OTS964, indisulam, GNF2133) that similarly downregulate OGT and OGA with distinct splicing profiles. These findings reveal previously unobserved splicing modulator chemotypes and approaches to disrupt O-GlcNAc homeostasis."

Journal • OGA • OGT

Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats. (PubMed, Front Aging Neurosci) - "Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • APP • GFAP • OGA

O-GlcNAcylation stabilizes c-MYC to upregulate xCT and inhibit ferroptosis in ovarian cancer. (PubMed, Life Sci) - "Our research may provide intervention strategies for the treatment of OV."

Journal • Oncology • Ovarian Cancer • Solid Tumor • GPX4 • MYC

Cross-Talk Between Tau O-GlcNAcylation and the Formation of the Early Driver of Neurodegeneration (Cis P-Thr231-Pro Tau) in Primary Cortical Neurons. (PubMed, Mol Neurobiol) - "Additionally, we observed that the Trans p-Tau conformation represents a normal conformer under physiological conditions. Collectively, our data support tau O-GlcNAcylation as a promising therapeutic strategy for Alzheimer's disease and other tauopathies."

Journal • Alzheimer's Disease • CNS Disorders • OGA • PTH2R

Safety, Tolerability, Pharmacokinetics, and Brain Target Occupancy of the OGA Inhibitor ASN90 in Healthy Participants. (PubMed, Mov Disord) - P2 | "The phase 1 results of ASN90 in healthy participants provide strong support for its further development in progressive supranuclear palsy (PSP) and AD. Currently, Ferrer Internacional, S.A. is conducting a phase 2 study, known as PROSPER (ClinicalTrials.gov ID: NCT06355531), to evaluate the efficacy, safety, and pharmacokinetics of ASN90 in slowing the progression of PSP."

Clinical • Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease • Progressive Supranuclear Palsy

Hyp-101 reduced tau-associated pathology and cognitive dysfunction via OGA inhibition. (Neuroscience 2025) - "In vivo, oral administration every other day-starting two weeks after intracerebral ventricular injection of streptozotocin significantly improved cognitive performance in mice, while increasing brain O-GlcNAc levels and reducing levels of hyperphosphorylated tau. These findings support the therapeutic potential of OGA inhibition as a strategy to alleviate tau-related pathology and cognitive deficits in Alzheimer's disease."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • OGA

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

Loss of Negative Metabolic Feedback Drives TET2 Mutant Inflammation (ASH 2024) - "In response to nutrient cues, TET2 physiologically binds OGT on chromatin thus restraining its activity. Upon TET2 loss, OGT binding to genomic loci is increased causing metabolic hyperactivity and lipid accumulation, ultimately driving inflammation."

Hematological Malignancies • Inflammation • Metabolic Disorders • Oncology • ACLY • KIT • OGT • TET2

Safety, Tolerability and Pharmacokinetics of a Novel Oral OGA Inhibitor (FNP-223) First-in-Human Phase 1 Study (MDS Congress 2025) - "Objective: To evaluate the safety, tolerability, and pharmacokinetics of FNP-223 (formerly ASN90) in healthy volunteers (HV). The findings indicate that FNP-223 is safe and well-tolerated at doses ranging from 100 to 500 mg, administered twice a day in HV. Additionally, the observed dose proportionality, along with the CSF-to-plasma ratios for both Cmax and AUC, suggests that the unbound fraction of the drug can effectively diffuse across the human blood-brain barrier. This study, along with PET-based target engagement assessments, supports the continued clinical development of FNP-223 in the ongoing Phase 2 PROSPER trial involving patients with PSP."

Clinical • First-in-human • P1 data • PK/PD data • CNS Disorders • Proteinopathy

OGA inhibition as a potential therapeutic approach for tauopathies: The prosper study, a phase 2 trial in PSP (EAN 2025) - "FNP-223 represents a promising therapeutic approach targeting tau pathology in PSP. The PROSPER study will determine its potential as a disease-modifying agent for PSP, addressing an urgent unmet need in this population."

P2 data • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy • OGA

Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers. (PubMed, Redox Biol) - "Functional improvements translated in enhanced recognition memory in Ts2Cje mice. Our study highlights the pivotal role of altered protein O-GlcNAcylation in DS neuropathology and establishes the molecular basis to envision the O-GlcNAc process as a promising therapeutic target to mitigate genetic- and metabolism-driven brain alterations linked to redox imbalance, mitochondrial failure and the development of AD features."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Genetic Disorders • Solid Tumor • OGA

FTO O-GlcNAcylation promotes TRIM21-mediated FTO ubiquitination degradation to sustain the negative feedback control of macrophage inflammation. (PubMed, Front Immunol) - "These findings reveal a mechanism that FTO O-GlcNAcylation promotes its ubiquitination degradation, and thus induces Socs1 m6A methylation and downregulates LPS-mediated inflammatory response, which maintains the negative feedback control of macrophage inflammatory cytokine storm in sepsis. Regulation of FTO O-GlcNAcylation may offer a potential therapeutic strategy for combating endotoxin-induced inflammatory disease and other FTO abnormal expression-associated diseases."

Journal • Genetic Disorders • Infectious Disease • Inflammation • Obesity • Septic Shock • Targeted Protein Degradation • FAT2 • FTO • IL1B • IL6 • SOCS1 • TNFA • TRIM21

In vivo quantification of [11C]BIO-1819578 in non-human primates, a novel radioligand for O-GlcNAcase. (PubMed, J Cereb Blood Flow Metab) - "The results showed that [11C]BIO-1819578 has suitable characteristics for reliable quantification of OGA using full kinetic modelling. The effective dose was on par with other 11C radioligands and is unlikely to pose an issue for human use."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • OGA

OGA INHIBITION AS A POTENTIAL THERAPEUTIC APPROACH FOR TAUOPATHIES: THE PROSPER STUDY, A PHASE 2 TRIAL IN PSP (ADPD 2025) - "FNP-223 is a promising disease -modifying therapy for PSP that is being studied to assess safety, tolerability, and efficacy in slowing disease progression in patients with PSP: the Phase 2 PROSPER study."

P2 data • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

EVIDENCE FOR OGA INHIBITION TO IMPACT NEURODEGENERATIVE PATHOLOGIES (ADPD 2025) - P1 | "Conclusions Nonclinical data indicated OGA inhibition has the potential to be an effective treatment for AD and suggested a manageable safety profile to move ceperognastat into clinical studies. However, lack of efficacy in a phase 2 study in early symptomatic AD suggests the potential for further clinical development needs to be considered carefully."

Alzheimer's Disease • Cardiovascular • CNS Disorders • OGA

OGA INHIBITION AS A POTENTIAL THERAPEUTIC APPROACH FOR TAUOPATHIES: THE PROSPER STUDY, A PHASE 2 TRIAL IN PSP (ADPD 2025) - "FNP-223 is a promising disease-modifying therapy for PSP that is being studied to assess safety, tolerability, and efficacy in slowing disease progression in patients with PSP: the Phase 2 PROSPER study."

P2 data • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy • OGA

Brain Transcriptome Changes Associated With an Acute Increase of Protein O-GlcNAcylation and Implications for Neurodegenerative Disease. (PubMed, J Neurochem) - "Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits."

Journal • Alzheimer's Disease • CNS Disorders • AMPK • OGA

An Efficient and Accessible Hectogram-Scale Synthesis for the Selective O-GlcNAcase Inhibitor Thiamet-G. (PubMed, ACS Omega) - "Herein is described a scalable method to produce Thiamet-G, a potent, selective, and widely used brain-permeable OGA inhibitor. This synthetic route begins with inexpensive precursor, requires no column chromatography, employs simple nontoxic reagents, and in a single campaign can furnish several hundred grams of crystalline Thiamet-G in an overall yield of 44% over six steps."

Journal • CNS Disorders • Oncology • OGA