TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase-ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound 29 revealed good brain penetration in vivo and was able to reduce TDP-43 phosphorylation not only in cell cultures but also in the spinal cord of transgenic TDP-43 mice. A shift to M2 anti-inflammatory microglia was also demonstrated in vivo. Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine 29 as a valuable lead compound for future ALS therapy.

• Authors: Vanesa Nozal, Loreto Martínez-González, Marta Gomez-Almeria, Claudia Gonzalo-Consuegra, Paula Santana, Apirat Chaikuad, Eva Pérez-Cuevas, Stefan Knapp, Daniel Lietha, David Ramírez, Sabrina Petralla, Barbara Monti, Carmen Gil, Angeles Martín-Requero, Valle Palomo, Eva de Lago, Ana Martinez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 2 Pg. 1585-1607 (01 27 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 34978799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Protein Kinase Inhibitors
• TARDBP protein, human
• tau-tubulin kinase
• Protein Serine-Threonine Kinases

Topics

• Amyotrophic Lateral Sclerosis (drug therapy)
• Animals
• Brain (drug effects, metabolism)
• Case-Control Studies
• DNA-Binding Proteins (metabolism)
• Humans
• Inflammation (drug therapy, metabolism, pathology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Phosphorylation
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Spinal Cord (drug effects, metabolism)
• Tissue Distribution