| Structural highlights
Disease
TTBK2_HUMAN Spinocerebellar ataxia type 11. The disease is caused by mutations affecting the gene represented in this entry.
Function
TTBK2_HUMAN Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro.[1] [2]
Publication Abstract from PubMed
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.
TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.,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 J Med Chem. 2022 Jan 27;65(2):1585-1607. doi: 10.1021/acs.jmedchem.1c01942. Epub , 2022 Jan 3. PMID:34978799[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bouskila M, Esoof N, Gay L, Fang EH, Deak M, Begley MJ, Cantley LC, Prescott A, Storey KG, Alessi DR. TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development. Biochem J. 2011 Jul 1;437(1):157-67. doi: 10.1042/BJ20110276. PMID:21548880 doi:http://dx.doi.org/10.1042/BJ20110276
- ↑ Goetz SC, Liem KF Jr, Anderson KV. The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell. 2012 Nov 9;151(4):847-858. doi: 10.1016/j.cell.2012.10.010. PMID:23141541 doi:http://dx.doi.org/10.1016/j.cell.2012.10.010
- ↑ 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. 2022 Jan 27;65(2):1585-1607. doi: 10.1021/acs.jmedchem.1c01942. Epub , 2022 Jan 3. PMID:34978799 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01942
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