Authors
Cecilia Sanchez-Santos, Alberto Jimenez-Amor, Loreto Martinez-Gonzalez, Vanesa Nozal, Raquel Martin-Morales, Elnaz Aledavood, Daniel Bausela, Kayla Merrigan, Karen Diaz-Palacios, Rezart Zhubi, Stefan Knapp, Francesc R Garcia-Gonzalo, Carmen Rodriguez-Cueto, Carmen Gil, Eva de Lago, Ana Martinez
Published in
Journal of medicinal chemistry. Volume 69. Issue 15. Pages 19451-19481. Aug 13, 2026.
Abstract
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.
PMID:
42593908
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.
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