TY - JOUR

T1 - Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases

T2 - A Structural Perspective

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

N1 - Funding Information: This work was supported by a grant from the National Science Center (UMO-2019/34/E/NZ1/00467) and by NAWA Polish Returns 2018 (PPN/PPO/2018/1/00046/U/00001) to A.C. The authors acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE FACILITY/2017-4/6 grant from the Foundation for Polish Science) for valuable support. The authors acknowledge Proteomics and Mass Spectrometry Core Facility of the Malopolska Center of Biotechnology for protein identification. X-ray data were collected at the HZB BESSY II 14.1 (Berlin, Germany) and P11 at DESY (Hamburg, Germany). The authors thank the synchrotron facilities for the allocation of beam time and also wish to thank Dr. Tony Fröhlich for the structural processing of the proteins in Schroedinger’s MAESTRO. Finally, the authors wish to thank Dr. Seung-Wook Chi and Dr. Sungchan Cho for kindly giving them access to a docked structure of CX-4945 in DYRK1A.

PY - 2023/3/23

Y1 - 2023/3/23

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85149711938&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.2c01887

DO - 10.1021/acs.jmedchem.2c01887

M3 - Article

C2 - 36883902

AN - SCOPUS:85149711938

VL - 66

SP - 4009

EP - 4024

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

SN - 0022-2623

IS - 6

ER -