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.

Adenine derivatives as inhibitors of the casein kinase CK1delta enzyme

Cescon, Eleonora;Federico, Stephanie;Spalluto, Giampiero;
2024-01-01

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/3072141
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