title: Pharmacokinetic characterization of CK2 inhibitor CX-4945.
abstract: Over-expression of protein kinase CK2 is highly linked to the survival of cancer cells and the poor prognosis of patients with cancers. CX-4945, a potent and selective orally bioavailable ATP-competitive inhibitor of CK2, inhibits the oncogenic cellular events such as proliferation and angiogenesis, and the increase of tumor growth in mouse xenograft model. In this study, the pharmacokinetic information about CX-4945 was provided; at 10 μM, CX-4945 with high stability in human and rat liver microsome exhibited low percentage of inhibition (<10 %) in CYP450 isoforms (1A2, 2C19, 3A4), but considerable inhibition (~70 %) in CYP450 2C9 and 2D6. In hERG potassium channel inhibition assay, CX-4945 exhibited relatively low inhibition rate. Additionally, CX-4945 showed high MDCK cell permeability (>10 × 10(-6) cm/s) and above 98 % of plasma protein binding in the rat. After intravenous administration, Vss (1.39 l/kg) and extremely low CL (0.08 l/kg/h) were observed. Moreover, orally administrated CX-4945 showed high bioavailability (>70 %) and these data might be related to the MDCK cell permeability results.
authors.affiliation: Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: You Hwa
authors.initials: YH
authors.lastname: Son
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009287:Naphthyridines / Q000493:pharmacokinetics*; D010619:Phenazines; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009287:Naphthyridines; D010619:Phenazines; C555142:silmitasertib; D047390:Casein Kinase II