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

A Structural Perspective

verfasst von

Przemyslaw Grygier, Katarzyna Pustelny, Jakub Nowak, Przemyslaw Golik, Grzegorz M. Popowicz, Oliver Plettenburg, Grzegorz Dubin, Filipe Menezes, Anna Czarna

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.

Organisationseinheit(en)

Zentrum für Biomolekulare Wirkstoffe (BMWZ)
Institut für Organische Chemie
Laboratorium für Nano- und Quantenengineering

Externe Organisation(en)

Jagiellonian University
Selvita S.A
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Technische Universität München (TUM)
Deutsches Zentrum für Diabetesforschung e.V. (DZD)
Institute for Lung Health (ILH)

Typ

Artikel

Journal

Journal of medicinal chemistry

Band

66

Seiten

4009-4024

Anzahl der Seiten

16

ISSN

0022-2623

Publikationsdatum

23.03.2023

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Molekularmedizin, Wirkstoffforschung

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1021/acs.jmedchem.2c01887 (Zugang: Offen)