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

• Published in: Journal of medicinal chemistry Vol. 65; no. 2; pp. 1585 - 1607
• Main Authors: Nozal, Vanesa, Martínez-González, Loreto, Gomez-Almeria, Marta, Gonzalo-Consuegra, Claudia, Santana, Paula, Chaikuad, Apirat, Pérez-Cuevas, Eva, Knapp, Stefan, Lietha, Daniel, Ramírez, David, Petralla, Sabrina, Monti, Barbara, Gil, Carmen, Martín-Requero, Angeles, Palomo, Valle, de Lago, Eva, Martinez, Ana
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.01.2022; Amer Chemical Soc
• Subjects: Amyotrophic Lateral Sclerosis - drug therapy; Animals; Brain - drug effects; Brain - metabolism; Case-Control Studies; Chemistry, Medicinal; DNA-Binding Proteins - metabolism; Humans; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Life Sciences & Biomedicine; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pharmacology & Pharmacy; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Rats; Rats, Wistar; Science & Technology; Spinal Cord - drug effects; Spinal Cord - metabolism; Tissue Distribution; MUTANT; COMPLEX; DOMAIN; PROTEIN; ACCURATE DOCKING; PHOSPHORYLATION; GLIDE; MODEL; TTBK1

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 (...