Proteostasis

The ALBORADA Drug Discovery Institute is focused on understanding and manipulating proteostasis.

Targeting proteostasis mechanisms for the treatment of neurodegeneration.

The ALBORADA Drug Discovery Institute is developing new approaches to slow or halt the progress of the diseases that cause dementia. Our primary focus is to explore mechanisms associated with the misfolded, aggregated proteins which characterise most neurodegenerative diseases.

There is strong evidence that the misfolded and oligomerised forms of proteins such as tau (Alzheimer’s disease and other tauopathies), huntingtin (Huntington’s disease) and α-synuclein (Parkinson’s disease, dementia with Lewy bodies) are key species responsible for driving the development of the diseases that cause dementia.

The ALBORADA Drug Discovery Institute (ADDI) is focussed on understanding and manipulating proteostasis – the mechanisms which control the levels, structure and toxicity of these proteins. We are working with academics who are exploring proteostasis pathways and mechanisms such as:

  • Factors affecting the overall levels of these proteins, particularly clearance mechanisms such as proteosomal clearance and autophagy, this latter process being capable of removing larger oligomeric or aggregated species. We are developing methods to increase the rate at which the misfolded proteins are cleared through these mechanisms.
  • The role of chaperone proteins that help the folding and unfolding of their client proteins. We are exploring approaches to increasing chaperone activity.
  • The role of post-translational modifications of these proteins which can affect rates of clearance and of aggregation. Can we learn how to control these modifications to reduce levels of the unwanted toxic species?
  • The response of cells to the stress associated with the build-up of unfolded proteins and the resultant impact on general proteostasis, known as the unfolded protein response, is known to be a critical factor in the toxicity associated with misfolded proteins.

We have an advanced drug discovery program seeking to develop inhibitors of the PI5P4 kinases. Lead Academic Scientist Prof David Rubinsztein has previously used genetic studies to show that blocking these enzymes upregulates autophagy, a natural cellular protein clearance mechanism which is capable of digesting and removing neurotoxic proteins. In cell models, blocking the activity of the enzymes reduced the effects of Huntington’s disease.

At the ALBORADA Drug Discovery Institute, we have identified small molecule inhibitors of the PI5P4 kinases and have shown in a range of cell types, including primary neurons, that these compounds upregulate autophagy. Hit molecules were identified through the screening of ADDI’s fragment library and a diversity library donated by Cancer Research UK, as well as through virtual screening. These hits have been further optimised into potent and selective PI5P4 kinase inhibitors with properties consistent with those of a drug, including oral bioavailability and brain penetration in rodents. In vivo studies are ongoing to test the effects of these autophagy modulators in animal models of neurodegeneration.