肌萎缩侧索硬化
化学
体内
激酶
小胶质细胞
磷酸化
神经科学
蛋白激酶A
药理学
细胞生物学
癌症研究
生物化学
生物
疾病
医学
免疫学
病理
炎症
生物技术
作者
Vanesa Nozal,Loreto Martínez-González,Marta Gómez‐Almería,Claudia Gonzalo‐Consuegra,Paula Santana,A. Chaikuad,Eva Pérez-Cuevas,Stefan Knapp,Daniel Lietha,David Ramírez,Sabrina Petralla,Barbara Monti,Carmen Gil,Ángeles Martín-Requero,Valle Palomo,Eva de Lago,Ana Martı́nez
标识
DOI:10.1021/acs.jmedchem.1c01942
摘要
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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