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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01942

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.