Therapeutics , Targets , and Chemical Biology CX-4945 , an Orally Bioavailable Selective Inhibitor of Protein Kinase CK 2 , Inhibits Prosurvival and Angiogenic Signaling and Exhibits Antitumor Efficacy

Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and nononcogenicproteins that are essential tomediate oncogene signaling and to support the alteredphysiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2a catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. Inmodels of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1a) transcription in cancer cells.Whenadministeredorally inmurinexenograft models, CX-4945waswell tolerated anddemonstrated robust antitumor activitywith concomitant reductionsof the mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling inmultiple pathways. Finally, CX-4945 is the first orally bioavailable small molecule inhibitor of CK2 to advance into human clinical trials, thereby paving the way for an entirely new class of targeted treatment for cancer. Cancer Res; 70(24); 10288–98. 2010 AACR.