Neurodegenerative disorders, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), pose an immense global health burden and significantly impacts patients’ quality of life. An estimated 150 million people are projected to be affected by dementia by 2050 without the development of disease-modifying interventions. The current lack of disease-modifying treatment options underscores the urgent need for research into novel therapeutics. The complex and multifaceted nature of these disorders presents a significant challenge in developing effective therapies, with numerous clinical trials failing due to insufficient efficacy or safety concerns.
This work has explored two distinct yet complementary approaches to address some of the hallmark pathological mechanisms underlying AD and FTD: modulating neuroinflammation through P2X7 receptor (P2X7R) antagonism and targeting pathological protein aggregates, specifically TDP-43 inclusions, through small molecule modulators and targeted protein degradation. The first approach investigated the development of novel P2X7R antagonists to attenuate neuroinflammation, a key contributor to AD pathogenesis. Structural modifications of lead compound 23 were performed, focusing on the linker region, to elucidate structure-activity relationships (SAR) and guide future optimisation strategies.
This work also delved into the identification and characterisation of small molecules capable of modulating TDP-43 proteinopathies, a hallmark pathology of FTD. High-throughput screening (HTS) efforts identified hit compound IKK-16 (93) 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 work facilitated the elucidation of key pharmacophore 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 Autophagy Targeting Chimeras (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 (175) provided proof-of-concept for this approach, while also revealing critical insights into the structural determinants for maintaining protein-ligand interactions.
Collectively, 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. By exploring approaches such as P2X7R antagonism, small molecule TDP-43 modulation, and targeted protein degradation, this work has contributed to the broader efforts in developing disease-modifying treatments for AD and FTD. The insights gained from these studies serve as a valuable foundation for future drug discovery efforts, offering new avenues for the development of effective therapeutics.