Identification of Novel Modulators for Neurodegenerative Disease States

Abstract

Neurodegenerative disorders, such as AD and FTD, pose an immense global health burden. The current lack of disease-modifying treatment options underscores the urgent need for research into novel therapeutics.

This thesis has explored two complementary approaches to address some of the hallmark pathological mechanisms underlying AD and FTD: modulating neuroinflammation through P2X7R antagonism and targeting TDP-43 inclusions, through small molecule modulators and targeted protein degradation. The first approach investigated the development of P2X7R antagonists to attenuate neuroinflammation, a key contributor to AD pathogenesis. Structural modifications of lead compound were performed to elucidate SAR trends and guide future optimisation efforts.

This work also delved into the identification and characterisation of small molecules capable of modulating TDP-43 proteinopathies. HTS efforts identified hit compound IKK-16 capable of reducing TDP-43 inclusions by 70%. The development of a scalable synthetic route enabled the generation of a diverse library of analogues. This facilitated the elucidation of key pharmacophoric features required for TDP-43 binding. This exploration has provided a foundation for the rational design of next-generation ligands to directly modulate TDP-43 pathology.

Building upon these findings, this investigation explored the potential of AUTACs as a novel therapeutic modality for the targeted degradation of pathological TDP-43 inclusions. The design, synthesis, and biological evaluation of Urolithin-based AUTACs provided proof-of-concept for this approach, while also revealing critical insights into the structural determinants for maintaining protein-ligand interactions.

Overall, this thesis aimed to advance the understanding of neuroinflammatory processes and pathological protein aggregation in neurodegenerative disorders, while also investigating novel therapeutic strategies to target these pathogenic mechanisms.