7QHW

TTBK1 kinase domain in complex with inhibitor 29

This is a non-PDB format compatible entry.

Summary for 7QHW

• Entry DOI: 10.2210/pdb7qhw/pdb
• Descriptor: Tau-tubulin kinase 1, ~{N}-[4-(4-chloranylphenoxy)phenyl]-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69264.79

Authors

Nozal, V.,Liehta, D. (deposition date: 2021-12-14, release date: 2022-10-26, Last modification date: 2024-01-31)

Primary citation

Nozal, V.,Martinez-Gonzalez, L.,Gomez-Almeria, M.,Gonzalo-Consuegra, C.,Santana, P.,Chaikuad, A.,Perez-Cuevas, E.,Knapp, S.,Lietha, D.,Ramirez, D.,Petralla, S.,Monti, B.,Gil, C.,Martin-Requero, A.,Palomo, V.,de Lago, E.,Martinez, A.
TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.
J.Med.Chem., 65:1585-1607, 2022

PubMed 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 revealed good brain penetration 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 . Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine as a valuable lead compound for future ALS therapy.

PubMed: 34978799
DOI: 10.1021/acs.jmedchem.1c01942

Experimental method

X-RAY DIFFRACTION (2.8 Å)