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

A Structural Perspective

authored by

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.

Organisation(s)

Centre of Biomolecular Drug Research (BMWZ)
Institute of Organic Chemistry
Laboratory of Nano and Quantum Engineering

External Organisation(s)

Jagiellonian University
Selvita S.A
Helmholtz Zentrum München - German Research Center for Environmental Health
Technical University of Munich (TUM)
German Center for Diabetes Research (DZD)
Institute for Lung Health (ILH)

Type

Article

Journal

Journal of medicinal chemistry

Volume

66

Pages

4009-4024

No. of pages

16

ISSN

0022-2623

Publication date

23.03.2023

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Molecular Medicine, Drug Discovery

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/acs.jmedchem.2c01887 (Access: Open)