[CAS NO. 1009820-21-6]  Silmitasertib (CX-4945)

CX-4945 is selective for CK2, as it only inhibits 7 of the 238 kinases by more than 90% at concentration of 0.5 μM, which is 500-fold greater than the IC50 of CK2. Although in cell-free systems CX-4945 inhibits FLT3, PIM1, and CDK1 with IC50 of 35 nM, 46 nM, and 56 nM, respectively, CX-4945 treatment at 10 μM is inactive against FLT3, PIM1, and CDK1 in cell-based functional assays. CX-4945 exhibits a broad spectrum of antiproliferative activity, and the breast cancer cell lines displays the widest range of sensitivity to CX-4945 with EC50 of 1.71-20.01 μM. The antiproliferative activity of CX-4945 correlates with CK2α mRNA and protein levels but not the CK2α' catalytic subunit, the regulatory CK2β subunit, and the PI3K/Akt or PTEN mutational status. CX-4945 inhibits PI3K/Akt signaling by directly blocking the phosphorylation of Akt at Serine 129 by CK2 rather than through activation of PTEN. CX-4945 treatment causes reduced phosphorylation of p21 (T145), increased levels of total p21 and p27, and induction of caspase 3/7 activity. CX-4945 treatment induces a G2/M cell-cycle arrest in BT-474 cells and a G1 arrest in BxPC-3 cells. CX-4945 inhibits HUVEC proliferation, migration, and tube formation with IC50 of 5.5 μM, 2 μM, and 4 μM, respectively. Under hypoxic conditions in BT-474 and BxPC-3 cells, CX-4945 treatment prevents downregulation of p53 and pVHL and reduces activation of HIF-1α transcription. CX-4945 potently inhibits endogenous intracellular CK2 activity with IC50 of 0.1 μM in Jurkat cells.