Casein Kinase 1δ Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders

: Casein kinase 1 (CK1) belongs to the serine-threonine kinase family and is expressed in all eukaryotic organisms. At least six human isoforms of CK1 (termed α, γ1-3, δ and ε) have been cloned and characterized. CK1 isoform modulates several physiological processes, including DNA damage repair, circadian rhythm, cellular proliferation and apoptosis. Therefore, CK1 dysfunction may trigger diverse pathologies, such as cancer, inflammation and central nervous system disorders. Overexpression and aberrant activity of CK1 has been connected to hyperphosphorylation of key proteins implicated in the development of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases and Amyotrophic Lateral Sclerosis. Thus, CK1 inhibitors have attracted attention as potential drugs for these pathologies and several compounds have been synthesized or isolated from natural sources to be evaluated for their CK1 inhibitory activity. Here we report a comprehensive review on the development of CK1 inhibitors, with a particular emphasis on structure-activity relationships and computational studies which provide useful insight for the design of novel inhibitors.