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

A clinical casein kinase 2 inhibitor, CX-4945 (silmitasertib), shows significant affinity toward the DYRK1A and GSK3fi 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/GSK3fi 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 GSK3fi with CX-4945. We built a quantum chemistry-based model to rationalize the compound affinity for CK2a, DYRK1A, and GSK3fi kinases. Our calculations identified a key element for CK2a's subnanomolar affinity to CX-4945. The methodology is expandable to other kinase selectivity modeling. We show that the inhibitor limits DYRK1A-and GSK3fi-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.

Automated summary

CX-4945 is a clinical casein kinase 2 inhibitor that has significant affinity towards DYRK1A and GSK3fi kinases, which are involved in various diseases. The crystal structures of DYRK1A and GSK3fi with CX-4945 were solved and analyzed, and a model was built to rationalize the compound affinity for CK2a, DYRK1A, and GSK3fi kinases. The inhibitor limits the activity of these kinases and shows potential for application in additional disease areas.