Neurological diseases—such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—are the leading cause of ill health, disability and premature death worldwide. These conditions affect 3.4 billion people globally, causing severe personal suffering and imposing an immense economic and societal burden on global communities. The vast complexity of these increasingly prevalent, devastating conditions presents a significant challenge to modern medicine and demands research into novel treatments.
This investigation explored the IKK-16 pharmacophore to address the unifying pathological hallmark of ALS and FTD: the neurotoxic aggregation of the TDP-43 protein. Previous work within the Kassiou group identified IKK-16 as a potent TDP-43 ligand, of which few others have been discovered.1 Systematic modification of the IKK-16 scaffold was performed, leveraging complementary strategies to optimize the synthesis of IKK-16 and a library of derivatives. These modifications yielded valuable insights into SAR trends governing TDP-43 binding. This work ultimately contributes to the broader development of therapeutics capable of modulating TDP-43 aggregation, advancing efforts toward curative treatments for FTD and ALS.
(1) Garrett, T. R. Identification of Novel Modulators for Neurodegenerative Disease States, The University of Sydney, 2025.