Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors

Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC50 = 0.08 mu M) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50 = 0.25 mu M). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including alpha-catenin/Akt pathway and PARP/Survivin pathway.

Automated summary

In this study, a series of chromone-2-aminothiazole derivatives were designed and synthesized as potential CK2 inhibitors. Compound 5i showed the strongest inhibitory activity against CK2 and exhibited potent anti-tumor activity. It induced apoptosis and inhibited downstream pathways of CK2 in HL-60 tumor cells.