Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide that responds poorly to existing therapies. The Casein kinase 1 (CK1) isoforms CK delta and CK1 epsilon are reported to be highly expressed in several tumor types, and both genetic and pharmacological inhibition of CK delta/epsilon activity has deleterious effects on tumor cell growth. IC261, an CK delta/epsilon selectively inhibitor, shows anti-tumor effect against pancreatic tumor and glioblastoma, but its role in HCC remains poorly characterized. In our research, IC261 displayed time- and dose-dependent inhibition of HCC cell proliferation, and induced G2/M arrest and cell apoptosis in vitro. However, the anti-tumor effects of IC261 was independent of CK delta/epsilon. Additionally, IC261 was verified to induce centrosome fragmentation during mitosis independent of CK delta status, and intraperitoneal injection of IC261 to HCCLM3 xenograft models inhibited tumor growth. Taken together, our data indicated that IC261 has therapeutic potential for HCC. (C) 2020 Published by Elsevier Inc.