2. Academic Validation
  3. TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy

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.
Vanesa Nozal 1 2,  Loreto Martínez-González 1 2,  Marta Gomez-Almeria 3,  Claudia Gonzalo-Consuegra 3,  Paula Santana 4,  Apirat Chaikuad 5 6,  Eva Pérez-Cuevas 1 2,  Stefan Knapp 5 6,  Daniel Lietha 1,  David Ramírez 7,  Sabrina Petralla 8,  Barbara Monti 8,  Carmen Gil 1,  Angeles Martín-Requero 1 2,  Valle Palomo 1 2,  Eva de Lago 2 3,  Ana Martinez 1 2
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas Margarita Salas─CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain.
  • 3 Instituto de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
  • 4 Facultad de Ingeniería, Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile el Llano Subercaseaux, 2801 San Miguel, Santiago, Chile.
  • 5 Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, Max von Lauestrasse 9, 60438 Frankfurt, Germany.
  • 6 Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max von Lauestrasse 15, 60438 Frankfurt, Germany.
  • 7 Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Víctor Lamas 1290, PO Box 160-C, 1290 Concepción, Chile.
  • 8 Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
PMID: 34978799 DOI: 10.1021/acs.jmedchem.1c01942
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 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.

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