Project - Drug discovery for diagnosis and treatment of frontotemporal dementia syndromes
All Chief investigators and associate investigators
- CIA: Dr Jonathan Danon
- AIA: Prof Michael Kassiou
- AIB: Dr Eryn Werry
- AIC: Dr Andrew Montgomery
Research Project Abstract
Frontotemporal dementia (FTD) is a common cause of early-onset dementia, with near comparable prevalence to Alzheimer’s disease (AD) for 45–55 year-olds. Drug discovery efforts to significantly stall, halt, or reverse brain damage have struggled badly over the past 20 years. Our research focuses on 1) developing molecular tools for studying the early stages of diseases like FTD (with potential for earlier diagnosis, aiding patient recruitment) and 2) discovery of new small molecules that reduce the damaging effects of protein aggregation in the CNS.
FTD, Alzheimer’s, ALS
Challenges within the field
There are currently no disease-modifying treatments for neurodegenerative diseases on the market. Our research program aims to provide better information for drug discovery scientists through development of more sensitive methods for early diagnosis of such diseases. We judiciously choose novel biological targets with therapeutic potential and use a combination of computational, medicinal chemistry, and pharmacology expertise to validate their role in neurodegeneration.
Research Project Description
The ultimate goals of this project are to discover novel chemical entities that display genuine translational promise for the diagnosis and treatment of FTD and other neurodegenerative diseases. To achieve these goals, we employ a multi-pronged approach encompassing medicinal chemistry, in silico modelling, and in vitro pharmacological testing. Projects include:
- Structure-based design of new drugs for restricting or halting the destructive effects of tau protein aggregation, either directly or through kinase activation/inhibition or chaperone manipulation
- Design and optimisation of new drugs for reducing or resolving TDP-43 protein aggregation, either directly or through chaperone manipulation
- Innovative discovery of sensitive and universal positron-emission tomography (PET) tracers for dissecting microglial contributions to FTD (e.g. pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes)
- Discovery of new small molecules that inhibit damaging neuroinflammatory pathways in the brains of FTD sufferers
- Discovery and development of novel PET radiotracers targeting different phenotypes of neuroinflammation
- Discovery of novel small molecules targeting pathological protein aggregation in neurodegenerative disease states
Key Publications from this project
Sokias, R.; Werry, E. L.; et al. Eur. J. Med. Chem. 2020, 207, 112725.