Understanding In Vitro Pathways to Drug Discovery for TDP-43 Proteinopathies.

The use of cellular models is a common means to investigate the potency of therapeutics in pre-clinical drug discovery. However, there is currently no consensus on which model most accurately replicates key aspects of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) pathology, such as accumulation of insoluble, cytoplasmic transactive response DNA-binding protein (TDP-43) and the formation of insoluble stress granules. Given this, we characterised two TDP-43 proteinopathy cellular models that were based on different aetiologies of disease.

First Nondiscriminating Translocator Protein Ligands Produced from a Carbazole Scaffold.

Development of neuroinflammation agents targeting the translocator protein (TSPO) has been hindered by a common single nucleotide polymorphism (A147T) at which TSPO ligands commonly lose affinity. To this end, carbazole acetamide scaffolds were synthesized and structure activity relationships elaborated to explore the requirements for high-affinity binding to both TSPO wild type (WT) and the polymorphic TSPO A147T. This study reports high binding affinity and nondiscriminating TSPO ligands.