Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on BBI608 for cancer therapy.

Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhibitors based on BBI608. Among them, compound A11 exhibited the most potent in vitro tumor cell growth inhibitory activities toward MDA-MB-231, MDA-MB-468 and HepG2 cells with IC50 values as low as 0.67 ± 0.02 μM, 0.77 ± 0.01 μM and 1.24 ± 0.16 μM, respectively. Fluorescence polarization (FP) assay validated the binding of compound A11 in STAT3 SH2 domain with the IC50 value of 5.18 μM. Further mechanistic studies indicated that A11 inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes CyclinD1 and C-Myc. Simultaneously, it induced cancer cell S phase arrest and apoptosis in a concentration-dependent manner. An additional in vivo study revealed that A11 suppressed the MDA-MB-231 xenograft tumor growth in mice at the dose of 10 mg/kg (i.p.) without obvious body-weight loss. Finally, molecular docking study further elucidated the binding mode of A11 in STAT3 SH2 domain.