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

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.