Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia
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All types of dementia, including Alzheimer's disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)-induced neuroinflammatory mouse model of dementia. Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer's disease and other types of dementia.
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Fosgo-AM, the active metabolite of Fosfogonimenton, in dementia animal models has demonstrated the capability to stimulate the HGF/MET system, activating synaptic plasticity and restoring cognitive function.
“Indeed, the Fosgo-AM, the active metabolite of Fosfogonimenton, in dementia animal models has already demonstrated the capability to stimulate the HGF/MET system activating synaptic plasticity and restoring cognitive function.”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [124]
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References 72 · Cited by 18
- Authors
- Johnston, J. L., Reda, S. M., Setti, S. E., Taylor, R. W., Berthiaume, A.-A., Walker, W. E., Wu, W., Moebius, H. J., & Church, K. J.
- Affiliations
- Athira Pharma (United States) (US)
- Corresponding author
- Church, Kevin J.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 20
- Issue
- 2
- Pages
- 431-451
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC10121968
- OpenAlex
- W4312019423
- Cited by
- 18
- References
- 72
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 7
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- HGF/MET signaling, positive modulators, Alzheimer's disease, dementia, neurotrophic effects, synaptogenesis, neurite outgrowth, neuroprotection, scopolamine-induced amnesia, lipopolysaccharide-induced neuroinflammation, prodrugs, cognitive impairment, hippocampal neurons, anti-inflammatory activity
- MeSH terms
- Alzheimer Disease, Animals, Hippocampus, Neurons, Signal Transduction, Hepatocyte Growth Factor, Mice, Rats
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