Fast Screening Strategy Identifies Potential New Inhibitors for Huntington’s Disease

Several small molecules have been identified by the Alborada Drug Discovery Institute as potential inhibitors to help halt the underlying mechanisms that drive the development of neurodegenerative diseases such as Huntington’s and Parkinson’s disease.

Silencing phosphatidylinositol 5-phosphate 4 (PI5P4) kinases has been shown to enhance the natural cleaning system of cells, called autophagy, according to previous research by David Rubinsztein, a professor and deputy director at the Cambridge Institute for Medical Research.

Strong evidence suggests that the buildup of abnormal proteins — including tau protein in Alzheimer’s disease, huntingtin in Huntington’s disease, and alpha-synuclein in Parkinson’s disease — is a key factor behind the loss of nerve cells that characterizes these disorders. Because PI5P4-kinases limit autophagy, blocking them with targeted molecules could boost the cells’ ability to clear away these toxic proteins.

Therefore, researchers from the Alborada Drug Discovery Institute — which was established by Alzheimer’s Research UK — used BioAscent’s on-demand compound library, called Compound Cloud, to perform a screening strategy for candidates that could inhibit the activity of PI5P4 kinases.

Users of the service can access information about 125,000 compounds and analyze their structures, along with other details. Researchers can select only the compounds that likely match their targets — in this case, PI5P4-kinases — which are then delivered ready for testing. This customized service cuts costs and time, because researchers screen from a pre-selected, narrower, and more promising list of candidates.

In January 2017, after analyzing a subset of 31,000 kinase inhibitors from Compound Cloud’s library, Alborada researchers selected 960 compounds as potential candidates, according to a press release.

Then they identified a number of small molecule inhibitors of PI5P4 kinases. The candidates — tested in several cell types grown in the lab, including primary neurons — have shown to enhance autophagy, thereby promoting the clearance of disease-linked neurotoxic proteins.

Researchers have further optimized their initial candidates, transforming them into more selective and potent PI5P4 kinase inhibitors. Moreover, the therapeutic properties of these inhibitors have also been optimized, including the ability to be given orally and to reach the brain of rodents.

These molecules are currently being tested in animal models of neurodegeneration to evaluate their potential as autophagy modulators.