2. Academic Validation
  3. Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective

Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective

  • J Med Chem. 2023 Mar 8. doi: 10.1021/acs.jmedchem.2c01887.
Przemyslaw Grygier 1,  Katarzyna Pustelny 1,  Jakub Nowak 1,  Przemyslaw Golik 2,  Grzegorz M Popowicz 3 4,  Oliver Plettenburg 5 6 7 8,  Grzegorz Dubin 1,  Filipe Menezes 3 4,  Anna Czarna 1
Affiliations

Affiliations

  • 1 Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland.
  • 2 Selvita S.A, Bobrzynskiego, 14, 30-338 Krakow, Poland.
  • 3 Institute of Structural Biology, Helmholtz Zentrum Muenchen, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
  • 4 Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Lichtenbergstrasse 4, Garching 85747, Germany.
  • 5 Institute of Medicinal Chemistry, Helmholtz Munich, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
  • 6 Institute of Organic Chemistry, Centre of Biomolecular Drug Research (BMWZ) and Laboratory of Nano and Quantum Engineering (LNQE), Leibniz University Hannover, Schneiderberg 1b, Hannover 30167, Germany.
  • 7 German Center for Diabetes Research (DZD), Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
  • 8 Institute of Lung Health (ILH), Aulweg 130, Giessen 35392, Germany.
PMID: 36883902 DOI: 10.1021/acs.jmedchem.2c01887
Abstract

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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