TY  - JOUR
AU  - Grygier, Przemyslaw
AU  - Pustelny, Katarzyna
AU  - Nowak, Jakub
AU  - Golik, Przemyslaw
AU  - Popowicz, Grzegorz M.
AU  - Plettenburg, Oliver
AU  - Dubin, Grzegorz
AU  - Menezes, Filipe
AU  - Czarna, Anna
TI  - Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 6
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - PUBDB-2023-07733
SP  - 4009 - 4024
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36883902
UR  - <Go to ISI:>//WOS:000947818200001
DO  - DOI:10.1021/acs.jmedchem.2c01887
UR  - https://bib-pubdb1.desy.de/record/600080
ER  -