Chemotype Exploration of Potential Tau Aggregation Therapeutics

Abstract

Taucentric therapeutics are now a strongly pursued area for the treatment of Alzheimer's Disease. Although tau-based therapeutics have mainly aimed to disrupt aggregation either directly or via kinase inhibition, tau-mediated neurodegeneration may potentially be a result of either soluble misfolded, hyperphosphorylated and/or mislocalised forms of tau. Molecular chaperones, such as heat shock proteins, are a family of polypeptides with upregulated expression during times of stress that ensure cells maintain an ability to regulate various processes of protein homeostasis. However, in the case of pathological events the processes by which protein undergoes quality control can lead to accumulation of misfolded protein, due to either a mutation or overwhelming quantities of client proteins. Heat shock protein 90 kDa (Hsp90) is one such example of a molecular chaperone that plays a fundamental role in homeostatic regulation, including mediation of tau. Unfortunately, the targeting of Hsp90 specifically has led to pharmacological issues due to the chemical structure of inhibitors, as opposed to their chemical target. The use of co-chaperones accompanying these heat shock proteins could allow for more specific targeting while modulating substantially lower processes and thus minimising off-target effects. To overcome this pharmacological barrier whilst minimising off target effects, the assessment of small molecular scaffolds and their structure-activity relationships (SAR) is important to achieve a greater understanding of potential treatments of tau aggregation through novel molecular chaperone targets. A promising scaffold has been identified as an inhibitor of the Hsp90-Aha1 complex. Using this lead molecular scaffold, a library of compounds has been designed and synthesised to investigate the SAR surrounding this novel target so as to determine the potential of these scaffolds as tau aggregation therapeutics.