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@ARTICLE{Grygier:600080,
author = {Grygier, Przemyslaw and Pustelny, Katarzyna and Nowak,
Jakub and Golik, Przemyslaw and Popowicz, Grzegorz M. and
Plettenburg, Oliver and Dubin, Grzegorz and Menezes, Filipe
and Czarna, Anna},
title = {{S}ilmitasertib ({CX}-4945), a {C}linically {U}sed
{CK}2-{K}inase {I}nhibitor with {A}dditional {E}ffects on
{GSK}3β and {DYRK}1{A} {K}inases: {A} {S}tructural
{P}erspective},
journal = {Journal of medicinal chemistry},
volume = {66},
number = {6},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {PUBDB-2023-07733},
pages = {4009 - 4024},
year = {2023},
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.},
cin = {DOOR ; HAS-User},
ddc = {610},
cid = {I:(DE-H253)HAS-User-20120731},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3)},
pid = {G:(DE-HGF)POF4-6G3},
experiment = {EXP:(DE-H253)P-P11-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36883902},
UT = {WOS:000947818200001},
doi = {10.1021/acs.jmedchem.2c01887},
url = {https://bib-pubdb1.desy.de/record/600080},
}