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Grygier, P.* ; Pustelny, K.* ; Nowak, J.* ; Golik, P.* ; Popowicz, G.M. ; Plettenburg, O. ; Dubin, G.* ; Cardoso Micu Menezes, F.M. ; Czarna, A.*

Silmitasertib (CX-4945), a clinically used CK2-kinase inhibitor with additional effects on GSK3β and DYRK1A kinases: A structural perspective.

J. Med. Chem. 66, 4009-4024 (2023)

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Open Access Green as soon as Postprint is submitted to ZB.

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A clinical casein kinase 2 inhibitor, CX-4945 (silmitasertib), shows significant affinity toward the DYRK1A and GSK3β kinases, involved in down syndrome phenotypes, Alzheimer's disease, circadian clock regulation, and diabetes. This off-target activity offers an opportunity for studying the effect of the DYRK1A/GSK3β kinase system in disease biology and possible line extension. Motivated by the dual inhibition of these kinases, we solved and analyzed the crystal structures of DYRK1A and GSK3β with CX-4945. We built a quantum-chemistry-based model to rationalize the compound affinity for CK2α, DYRK1A, and GSK3β kinases. Our calculations identified a key element for CK2α's subnanomolar affinity to CX-4945. The methodology is expandable to other kinase selectivity modeling. We show that the inhibitor limits DYRK1A- and GSK3β-mediated cyclin D1 phosphorylation and reduces kinase-mediated NFAT signaling in the cell. Given the CX-4945's clinical and pharmacological profile, this inhibitory activity makes it an interesting candidate with potential for application in additional disease areas.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Glycogen-synthase Kinase-3; Dependent Protein-kinase; Basis-sets; Selective Inhibitor; Magic Bullets; Design; Phosphorylation; Efficient; 3-beta; Drugs

ISSN (print) / ISBN 0022-2623

e-ISSN 1520-4804

Journal Journal of Medicinal Chemistry

Quellenangaben Volume: 66, Issue: 6, Pages: 4009-4024

Publisher American Chemical Society (ACS)

Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)
Institute of Medicinal Chemistry (IMC)

Grants Foundation for Polish Science
NAWA Polish Returns 2018
National Science Center