title: CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy.
abstract: Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic 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 CK2α 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. In models of angiogenesis, 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. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of 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 in multiple 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.
authors.affiliation: Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, CA 92121, USA. adamsj@cylenepharma.com
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: Peter
authors.initials: P
authors.lastname: Chua
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Josh
authors.initials: J
authors.lastname: Bliesath
authors.forename: Mayuko
authors.initials: M
authors.lastname: Omori
authors.forename: Nanni
authors.initials: N
authors.lastname: Huser
authors.forename: Caroline
authors.initials: C
authors.lastname: Ho
authors.forename: Chris
authors.initials: C
authors.lastname: Proffitt
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; C555142:silmitasertib; D047390:Casein Kinase II