CX-4945 (CX 4945) is a potent and selective ATP-competitive small molecule protein kinase CK2 inhibitor with a Ki and an IC50 of 0.38 and 1 nM for recombinant human CK2α, respectively. CX-4945 (CX 4945) has broad spectrum anti-proliferative activity in multiple cancer cell lines. The antiproliferative activity of CX-4945 (CX 4945) against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 (CX 4945; Silmitasertib) was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 (CX 4945) suppresses Akt signaling and inhibits proliferation of HUVEC Cells. CX-4945 (CX 4945) caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 (CX 4945) inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. Collectively, CX-4945 (CX 4945) inhibits pro-angiogenic CK2 signaling in vitro and in vivo.