The Science

ATH434 is the first of a new generation of small molecules from the quinazolinone class of drugs that was specifically designed to block the accumulation and aggregation of α-synuclein. α-synuclein is an abundant brain protein widely believed to be involved in the pathogenesis of Parkinson’s disease and certain types of atypical parkinsonism such as Multiple System Atrophy or Dementia with Lewy Bodies.

ATH434 is the first of a new generation of small molecules from the quinazolinone class of drugs that was specifically designed to block the accumulation and aggregation of α-synuclein. α-synuclein is of great interest because aggregated forms of the protein are considered a pathological hallmark of Parkinsonian conditions and are a recognised therapeutic target by neuroscientists and clinicians.

ATH434 has been shown in preclinical models to block α-synuclein accumulation and to prevent the loss of neurons in the region of the brain primarily affected in Parkinson’s disease, called the substantia nigra. This was demonstrated in several Parkinson’s disease animal models, including tests in transgenic mice that produce excessive amounts of the α-synuclein protein. Finkelstein, et al. Acta Neuropathol Commun 2017; 5: 53.

Experiments in an animal model of Multiple System Atrophy have also demonstrated the robust efficacy of ATH434. This animal model reproduces the key pathology of human Multiple System Atrophy – abundant clumps of α-synuclein inside oligodendroglial cells referred to as “glial cell inclusions”. Oligodendroglial cells have a vital support function in the brain to protect and nourish neurons. In addition, they scavenge abnormal α-synuclein released from diseased neurons. ATH434 was shown to reduce both oligomeric and aggregated forms of α-synuclein and prevent α-synuclein accumulation in affected oligodendroglial cells. Importantly, the beneficial effect on α-synuclein led to the preservation of neurons and improved motor function of treated animals.

Increased labile iron has been implicated in the pathology of α-synuclein related diseases, such as Parkinson’s disease and Multiple system atrophy (Oakley, et al. Neurology 2007;68:1820–1825. Berg and Youdim. Top Magn Reson Imaging 2006;17;5-17. Kaindlstorfer et al. Journal of Alzheimer’s Disease 61 (2018) 1253–1273). A novel approach for treating these diseases is to reduce labile iron that is causing iron-mediated accumulation and aggregation of α-synuclein, thereby preserving neurons and improving function (Crielaard et al., Nat Rev Drug Discov. 2017 Jun; 16 (2):400-423. Elkouzi et al. Nature Reviews Neurology 2019; 15: 204–223.). ATH434 is thought to act by binding and redistributing labile iron in this manner, but to not interfere with normal, tightly bound iron involved in oxygen transport, energy production and enzyme activity. Benefits of binding labile iron include reducing pathological protein accumulation and its sequelae as well as silencing processes that lead to oxidative stress.

Published Scientific Research

Drug discovery program

Key to maintaining a competitive advantage in the field is the ability for continuous improvement and innovation in the discovery of novel product candidates. The Alterity research team is evaluating new chemical scaffolds that offer mechanisms of action to intercede in disease processes. Using structure-activity relationship insights that have been developed over years of testing and validation by Alterity scientists, innovative patentable chemical compounds are being generated. These compounds are initially screened for activity in biological systems relevant to candidate diseases we are targeting. New screens are being investigated that will assess the ability of a compound to intercede in the pathogenic steps thought to underlie the target disease process, such as protein aggregation and hyperphosphorylation as well as downstream activities such as oxidative stress and cell death. Promising candidates arising from the Translational Research program will be progressed in relevant animal models of Parkinsonian diseases, Alzheimer’s disease or other neurodegenerative diseases.