• Target Hits for Neurodegenerative Disease Promising
    BioAscent’s COO, Sylviane Boucharens

News & Views

Target Hits for Neurodegenerative Disease Promising

Feb 24 2019

In partnership with Alzheimer’s Research UK the Alborada Drug Discovery Institute at the University of Cambridge has used BioAscent’s Compound Cloud library as part of its virtual screening programme to assess promising leads against a novel Huntington’s disease target. Focused primarily on mechanisms associated with the misfolded, aggregated proteins which characterise most neurodegenerative diseases, the Institute’s drug discovery program is seeking to develop inhibitors of the PI5P4 kinases. Other approaches used on compounds from a variety of sources have also included fragment screening and diversity screening.

Lead Academic Scientist Professor 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.

The institute downloaded the structures of the 31,000 kinase inhibitor subset of the Compound Cloud library which, after use of a number of computational methods, were assigned to 960 clusters. From this target-base, the institute was able to identify small molecule inhibitors of the PI5P4 kinases and have shown in a range of cell types, including primary neurons, that these compounds upregulate autophagy.

The most advanced hits in this program, said to be based on the initial Compound Cloud 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.

BioAscent’s COO, Sylviane Boucharens, was included in the BioBeat 2018 list of 50 Movers and Shakers in BioBusiness. Her nomination followed an incredibly successful year during 2018 in which she has spearheaded the company’s expansion to become a fully integrated drug discovery CRO.


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