Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.