A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3).

The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC50 values of 0.22, 0.49, 0.07 and 0.14 μM, respectively, which was over 10-fold more potent than napabucasin. Treatment with compound 8q decreased protein expression level of total STAT3 and p-STAT3Y705in vitro. The binding of compound 8q with STAT3 were further validated by electrophoretic mobility shift assay and surface plasmon resonance analysis. Compound 8q has a KD of 110.2 nM for full-length STAT3 recombinant protein. Moreover, the aqueous solubility of 8q was over 4.5-fold than that of napabucasin. In addition, compound 8qin vivo significantly reduced tumor growth compared to untreated mice, and exhibited good safety profile, indicating its great potential as an efficacious drug candidate for oncotherapy.