Name: ASN120290
Synonyms: ASN-561
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 1)
Company: Asceneuron SA


ASN120290 is an inhibitor of O-GlcNAcase, the glycoside hydrolase enzyme that removes O-linked N-acetylglucosamine (N-GlcNAc) from proteins. The function of numerous proteins is regulated by O-linked glycosylation of serine and threonine residues, which is reversed by O-GlcNAcase. 

N-GlcNAcylation of the microtubule-associated protein tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). A similar anti-aggregation effect of O-GlcNAc modification was recently reported for α-synuclein protein (Levine et al., 2019).

By increasing tau glycosylation, inhibitors of the O-GlcNAcase enzyme appear to stabilize tau in a soluble, nonpathogenic form. It is being developed as a potential treatment for progressive supranuclear palsy and other tau-related dementias.

In two different mouse strains expressing P301L mutant human tau, the OGA inhibitor thiamet G was reported to increase N-GlcNAc-modified tau, reduced tau neurofibrillary tangle numbers, and decreased neuronal cell loss (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment of a third mutant tau strain resulted in better motor skills, higher body weight, and longer lifespan, but no detectable tau glycosylation (Borghgraef et al., 2013).

No preclinical results have been formally published with ASN120290, previously known as ASN-561. Animal data presented at meetings indicated it penetrates the blood-brain barrier better than thiamet G. In P301L human tau mice, the compound reportedly evokes a 12-fold increase in brain tau O-GlcNAcylation, a 40 percent reduction in insoluble paired helical filaments, and 80 percent fewer neurofibrillary tangles (Aug 2014 conference news; Apr 2017 conference news).


In 2017, Asceneuron conducted a randomized, placebo-controlled Phase I safety and tolerability study of oral ASN120290 in healthy adult and aged volunteers. As presented at the AAIC in July 2018, it enrolled 61 subjects, who received single ascending doses, or multiple doses for up to 10 days (see abstract). The drug was reported to be have been well tolerated at single doses of up to 1,000 mg, or 500 mg twice a day. No dose-limiting toxicities, severe adverse events, or dropouts due to adverse events were reported. Plasma pharmacokinetics were dose-proportional and affected by food. In aged participants, ASN120290 rapidly appeared in the cerebrospinal fluid after dosing, at concentrations similar to those in plasma.

In July 2018, ASN120290 received orphan drug designation by the U.S. FDA for treatment of the primary tauopathy, progressive supranuclear palsy.

In November 2018, the company announced a trial using PET imaging with labeled ASN120290. This study will assess target engagement by quantifying binding of a radioactive ASN120290 tracer in the brains of healthy volunteers, both alone and after pre-administration of the inhibitor (see press release).

Clinical studies of ASN120290 are not yet listed in or other registries.

Last Updated: 18 Mar 2020


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News Citations

  1. Therapies Take Aim at Tau
  2. Treating Tau: Finally, Clinical Candidates Are Stepping into the Ring

Paper Citations

  1. . Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm. 2005 Jun;112(6):813-38. PubMed.
  2. . O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9. PubMed.
  3. . α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson's disease. Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1511-1519. Epub 2019 Jan 16 PubMed.
  4. . Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Apr;8(4):393-9. PubMed.
  5. . Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy. Neuropharmacology. 2014 Apr;79:307-13. Epub 2013 Dec 8 PubMed.
  6. . Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017 May 18;12(1):39. PubMed.
  7. . Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice. PLoS One. 2013;8(12):e84442. Epub 2013 Dec 23 PubMed.

External Citations

  1. abstract
  2. orphan drug designation
  3. press release

Further Reading


  1. . O-GlcNAcylation as a Therapeutic Target for Alzheimer's Disease. Neuromolecular Med. 2020 Jun;22(2):171-193. Epub 2020 Jan 1 PubMed.
  2. . Generation and characterization of a rabbit monoclonal antibody site-specific for tau O-GlcNAcylated at serine 400. FEBS Lett. 2013 Nov 15;587(22):3722-8. Epub 2013 Oct 7 PubMed.
  3. . O-GlcNAcylation of truncated NAC segment alters peptide-dependent effects on α-synuclein aggregation. Bioorg Chem. 2020 Jan;94:103389. Epub 2019 Nov 9 PubMed.
  4. . O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease. ACS Chem Neurosci. 2019 May 15;10(5):2209-2221. Epub 2019 Apr 26 PubMed.
  5. . O-GlcNAcylation and neurodegeneration. Brain Res Bull. 2016 Aug 4; PubMed.
  6. . Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro. Brain Res Bull. 2020 Mar;156:76-85. Epub 2020 Jan 10 PubMed.
  7. . The Role of Insulin Resistance and Protein O-GlcNAcylation in Neurodegeneration. Front Neurosci. 2019;13:473. Epub 2019 May 9 PubMed.
  8. . Sugar Kick Prevents Memory Impairment. J Med Chem. 2019 Nov 27;62(22):10059-10061. Epub 2019 Oct 31 PubMed.