Speedy Screening System Identifies New Potential PI5P4 Inhibitors for Huntington Disease

John Skidmore, DPhil, BA, the chief scientific officer at the ADDI

John Skidmore, DPhil

The ALBORADA Drug Discovery Institute (ADDI) has identified a number of small molecule inhibitors with the potential to halt the underlying mechanisms which drive the development of Huntington disease and Parkinson disease, among other conditions.¹

Using the Compound Cloud, an on-demand compound library developed by BioAscent, the researchers from the ADDI performed a screening strategy for candidates which could inhibit the phosphatidylinositol 5-phosphate 4 (PI5P4) kinases. Research from the Cambridge Institute for Medical Research conducted by its deputy director and professor David Rubinsztein, MBChB, PhD, and colleagues, has suggested that when PI5P4 kinases are silenced, it can enhance autophagy. This, in turn, aids in the digesting and removing neurotoxic proteins. In cell models, blocking the activity of the enzymes have reduced the effects of Huntington disease.

"As a drug discovery institute, we at ALBORADA screen compounds from a variety of sources," Steve Andrews, PhD, the head of Chemistry at the institute, explained to NeurologyLive. "We have some of our own in-house libraries and sometimes we source external libraries through collaboration or purchasing. In the case of the Compound Cloud, we were attracted to properties of one of the particular sub-libraries which aligned with the target we were interested in, as well as the competitive nature of the pricing."

The Compound Cloud consists of data for approximately 125,000 compounds, which researchers can then use to analyze structures and other details. The process ultimately saves time and costs, as screenings can be conducted from a pre-selected and more narrowed list of candidates.

The ADDI team used this method to analyze a subdivision of 31,000 kinase inhibitors from the library, selecting 960 potential candidates by filtering based on sub-structures, docking approaches using a literature crystal structure, and pharmacophore approaches based on known ligands of similar targets.

“The institute has now 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,” according to BioAscent. The most advanced hits were based on the initial Compound Cloud hits, which were then further optimized into “potent and selective PI5P4 kinase inhibitors with properties consistent with those of a drug, including oral bioavailability and brain penetration in rodents.”

"This work is at a relatively early stage of the drug discovery process and the compounds are not ready for clinical testing," Andrews said. "At ALBORADA Drug Discovery Institute we are pursuing a number of biological targets and pathways as a possible mechanism to treat the underlying causes of dementia. Our portfolio is focussed on proteostasis mechanisms and you can learn more about this on our website."

Currently, in vivo studies are ongoing to test the effects of these autophagy modulators in animal models of neurodegeneration. John Skidmore, DPhil, BA, the chief scientific officer at the ADDI, told the Video Journal of Dementia at the 2018 Alzheimer's Research UK Conference, in London, that while at the time they were only conducting in vitro studies, the ADDI was seeking to move very rapidly” into animal model studies, and that they anticipated conducting those experiments “in the coming years.”²

According to the ADDI, it is focused “on understanding and manipulating proteostasis —the mechanisms which control the levels, structure and toxicity” of the misfolded and oligomerized forms of tau, huntingtin, and a-synuclein proteins.³ It is currently working with researchers who are exploring proteostasis pathways and mechanisms, including proteasomal clearance and autophagy and their impact on overall protein levels, the role of chaperone proteins, the role of post-translational modifications of the previously mentioned proteins, and the response to cells associated with their buildup.

“One of the things that’s most exciting about the proteostatic mechanisms is that some of them can be quite specific to a protein,” Skidmore told the Video Journal of Dementia in 2018. “If you were looking at, for example, the effects of a particular post-translational modification on a particular protein, that would be specific, but others, such as enhancing clearance through, say, autophagy, are actually very general. It’s quite possible that you might clear huntingtin as well as, say, tau. You could have an effect on more than 1 disease.”

"The next stages are to iteratively improve these molecules and test them in models of increasing complexity. Further down the line, we hope to take advanced compounds into clinical trials," Andrews said.

REFERENCES

1. ALBORADA Drug Discovery Institute identifies advanced Huntington’s leads using BioAscent’s Compound Cloud library [press release]. Newhouse, UK: BioAscent Discovery; Published January 31, 2019. biospace.com/article/alborada-drug-discovery-institute-identifies-advanced-huntington-s-leads-using-bioascent-s-compound-cloud-library. Accessed February 11, 2019.

2. Targeting proteostasis for the treatment of neurodegenerative diseases. VJ Dementia YouTube channel. Published April 6, 2018. youtube.com/watch?v=8jEiZDpkIPc. Accessed February 12, 2019.

3. Proteostasis: The ALBORADA Drug Discovery Institute is focused on understanding and manipulating proteostasis. ADDI website. cambridge-ddi.alzheimersresearchuk.org/research/proteostasis. Accessed February 11, 2019.