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Adenine derivatives as inhibitors of the casein kinase CK1delta enzyme

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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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Acknowledgements

This research was funded by Italian Ministry of University and Research, call PRIN 2017, grant number 2017MT3993_004.

Author contributions

A.S., C.C., C.L., and D.D.B. designed the study, synthesized the compounds, performed the modeling studies, and wrote the manuscript with help from all co-authors. E.C. and S.F. performed the biological assays. M.B., G.M., G.S., and R.V. supervised the work and critically reviewed the manuscript. All authors approved the final manuscript.

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Authors and Affiliations

  1. School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, 62032, Camerino, MC, Italy

    Andrea Spinaci, Catia Lambertucci, Cui Chang, Michela Buccioni, Gabriella Marucci, Diego Dal Ben & Rosaria Volpini

  2. Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy

    Eleonora Cescon, Stephanie Federico & Giampiero Spalluto

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  1. Andrea Spinaci
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  9. Diego Dal Ben
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Correspondence to Diego Dal Ben.

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Spinaci, A., Lambertucci, C., Chang, C. et al. Adenine derivatives as inhibitors of the casein kinase CK1delta enzyme. Med Chem Res 33, 611–619 (2024). https://doi.org/10.1007/s00044-024-03202-6

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