Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on related heterocycle-fused naphthoquinones for cancer therapy

Abstract

Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore it is a potential therapeutic target for cancer treatment. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhibitors based on iso-napabucasin. Among them, compound A14 exhibited the most potent in vitro tumor cell growth inhibitory activities against HepG2 and K562 cells with IC₅₀ values as low as 0.88 μM and 2.16 μM, respectively. Compound A14 has a moderate percentage of plasma protein binding in vitro (88.6%), good plasma stability and solubility. After oral administration, the bioavailability of A14 was 44.22%. Finally, molecular docking and WB studies further clarified the binding mode of A14 in STAT3 SH2 domain.