A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting Aurora B kinase activity

Abstract

Aurora kinases play a key role in the regulation of mitosis and have been regarded as promising targets of cancer therapy. In this paper we describe a thienopyrimidine derivative (S7), a novel potent ATP-competitive hit inhibitor of Aurora B kinase screened through a HTS system, with the IC50 141.12 nM in the biochemical kinase activity assay. Human tumor cells treated with S7 showed dose-dependent inhibition of auto-phosphorylation of Aurora B on Thr232 and another widely-used marker specific for Aurora B kinase, the phosphorylation of Histone H3 (Ser 10), demonstrating endogenous Aurora B kinase activity were inhibited at cellular level. Moreover, S7 treatment induced proliferation inhibition, colony formation inhibition and apoptosis of human tumor cell lines in a dose- and time-dependent manner.

Keywords: 2-(5-phenylthieno [2,3-d] pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline; ATP-competitive; Apoptosis; Aurora B; Growth inhibition; HTS; IC(50); Molecular modeling; PhAurB (Thr232); PhH3 (Ser 10); S7; Small-molecule inhibitor; high throughput screening; inhibitory concentration (50%); phospho-Aurora B (Thr232); phospho-histone H3 (Ser 10).