Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.
Overview
- Centro de Investigaciones Biologicas “Margarita Salas”CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Avda. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
- Instituto de Investigaciones Biomédicas “Sols-Morreale”UAM/CSIC, Arturo Duperier 4, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Avda. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany
- Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- rcsb.org/
structure/ , at PDB; found in “Data Availability Statement”31ho - rcsb.org/
structure/ , at PDB; found in “Data Availability Statement”31hp - rcsb.org/
structure/ , at PDB; found in the text, “Introduction”4btj - rcsb.org/
structure/ , at PDB; found in the text, “X-ray Data Collection and Structure…”7q8w
Data Availability Statement
The coordinates and structure factors of TTBK1 and TTBK2 in complex with compound 62 have been deposited in the Protein Data Bank (PDB) under accession numbers 31HO (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 3, 28 September 2026
- Publisher: n/a → American Chemical Society
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 12 MeSH terms, 4 funders, 58 references.
Cite
This paper
Sanchez-Santos, C., Jimenez-Amor, A., Martinez-Gonzalez, L., Nozal, V., Martin-Morales, R., Aledavood, E., Bausela, D., Merrigan, K., Diaz-Palacios, K., Zhubi, R., Knapp, S., Garcia-Gonzalo, F. R., Rodriguez-Cueto, C., Gil, C., de Lago, E., & Martinez, A. (2026). Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy. Journal of medicinal chemistry, 69(15), 19451-19481. https://
BibTeX
@article{sanchezsantos20
author = {Sanchez-Santos, Cecilia and Jimenez-Amor, Alberto and Martinez-Gonzalez, Loreto and Nozal, Vanesa and Martin-Morales, Raquel and Aledavood, Elnaz and Bausela, Daniel and Merrigan, Kayla and Diaz-Palacios, Karen and Zhubi, Rezart and Knapp, Stefan and Garcia-Gonzalo, Francesc R and Rodriguez-Cueto, Carmen and Gil, Carmen and de Lago, Eva and Martinez, Ana},
title = {{Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy}},
journal = {Journal of medicinal chemistry},
year = {2026},
month = aug,
volume = {69},
number = {15},
pages = {19451--19481},
publisher = {American Chemical Society},
issn = {0022-2623},
doi = {10.1021/
url = {https://
pmid = {42593908},
pmcid = {PMC13492379}
}
RIS
TY - JOUR
AU - Sanchez-Santos, Cecilia
AU - Jimenez-Amor, Alberto
AU - Martinez-Gonzalez, Loreto
AU - Nozal, Vanesa
AU - Martin-Morales, Raquel
AU - Aledavood, Elnaz
AU - Bausela, Daniel
AU - Merrigan, Kayla
AU - Diaz-Palacios, Karen
AU - Zhubi, Rezart
AU - Knapp, Stefan
AU - Garcia-Gonzalo, Francesc R
AU - Rodriguez-Cueto, Carmen
AU - Gil, Carmen
AU - de Lago, Eva
AU - Martinez, Ana
TI - Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy
T2 - Journal of medicinal chemistry
J2 - J Med Chem
PY - 2026
DA - 2026/
VL - 69
IS - 15
SP - 19451
EP - 19481
SN - 0022-2623
PB - American Chemical Society
DO - 10.1021/
UR - https://
LA - en
ER -
CSL-JSON
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