Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer

Abstract

Inhibition of the signal transducer and activator of transcription 3 (STAT3) signalling pathway has been considered as a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we screened 1563 compounds and identified Bt354 as a new small-molecule inhibitor of the STAT3 signalling pathway. The effect of Bt354 on STAT3 activity was initially screened and Bt354 significantly inhibited STAT3 activity in a dual luciferase assay. Bt354 inhibited the proliferation of cancer cells in a dose- and time-dependent manner. The phosphorylation of STAT3 at Y705 was suppressed without affecting the phosphorylation of STAT3 at S727 in breast cancer cells. Furthermore, Bt354 inhibited the nuclear translocation of STAT3 and consequently induced cell growth inhibition, apoptosis and cell cycle G2/M arrest in triple negative breast cancer cells. In vivo, Bt354 also inhibited tumour growth in MDA-MB-435 and MDA-MB-231 xenograft mice without affecting body weight. Computational modelling showed that Bt354 could bind to the SH2 domain of STAT3. These findings suggest that Bt354 may be a potent anticancer agent for STAT3-activated triple negative breast cancer cells.