4-(benzylsulfanyl)thieno[2-3-d]pyrimidine and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Aggregates of the nuclear protein TDP-43 have been recognized as a hallmark of proteinopathy in both familial and sporadic cases of ALS. Post-translational modifications of this protein, include hyperphosphorylation, cause disruption of TDP-43 homeostasis and as a consequence, promotion of its neurotoxicity. Among the kinases involved in these changes, cell division cycle kinase 7 (CDC7) plays an important role by directly phosphorylating TDP-43. In the present manuscript the discovery, synthesis, and optimization of a new family of selective and ATP-competitive CDC7 inhibitors based on 6-mercaptopurine scaffold are described. Moreover, we demonstrate the ability of these inhibitors to reduce TDP-43 phosphorylation in both cell cultures and transgenic animal models such as C. elegans and Prp-hTDP43 (A315T) mice. Altogether, the compounds described here may be useful as versatile tools to explore the role of CDC7 in TDP-43 phosphorylation and also as new drug candidates for the future development of ALS therapies.

Topics: Amyotrophic Lateral Sclerosis; Animals; Behavior, Animal; Cell Cycle Proteins; DNA-Binding Proteins; Dose-Response Relationship, Drug; Humans; Mice; Mice, Transgenic; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Recombinant Proteins; Structure-Activity Relationship; Tumor Cells, Cultured