Discovery of N-substituted sulfamoylbenzamide derivatives as novel inhibitors of STAT3 signaling pathway based on Niclosamide.

Signal transducer and activator of transcription 3 (STAT3) has been confirmed as an attractive therapeutic target for cancer therapy. Herein, we designed and synthesized a series of N-substituted Sulfamoylbenzamide STAT3 inhibitors based on small-molecule STAT3 inhibitor Niclosamide. Compound B12, the best active compound of this series, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 0.61-1.11 μM in MDA-MB-231, HCT-116 and SW480 tumor cell lines with STAT3 overexpression, by inhibiting the phosphorylation of STAT3 of Tyr705 residue and the expression of STAT3 downstream genes, inducing apoptosis and inhibiting the migration of cancer cells. Furthermore, in vivo study revealed that compound B12 suppressed the MDA-MB-231 xenograft tumor growth in nude mice at the dose of 30 mg/kg (i.g.), which has better antitumor activity than the positive control Niclosamide. More importantly, B12 is an orally bioavailable anticancer agent as a promising candidate for further development.