Adenine derivatives as inhibitors of the casein kinase CK1delta enzyme

Overexpression of CK1δ has been associated to the development of cancer and neurodegenerative disorders, making ligands of this protein very promising drug candidates for the treatment these diseases and/or pharmacological tools for their study. A screening campaign of an in-house adenine derivative library revealed that some compounds are able to inhibit the CK1δ enzyme isoform with IC₅₀ in the low µM range. Molecular docking analyses were performed at a X-ray structure of the enzyme, leading to the rational design of novel di- and tri-substituted adenines that were synthesized and characterized. Biological evaluation demonstrated that the new compounds are endowed with moderate CK1δ inhibitory activity. In particular, the 2-amino-9-benzyladenine (12) and its 8-bromo derivative 14, tested at a concentration of 40 µM, inhibited the enzyme leaving a residual activity of about 35% and 42%, respectively. Docking studies provided an interpretation of these data, with suggestions for a further development of these compounds to achieve more potent CK1δ inhibitors.