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Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound <b>NK3</b> demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC₅₀ = 0.06 μM), leading to its selection for further investigation. The direct interactions between compound <b>NK3</b> and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound <b>NK3</b> revealed key interactions between <b>NK3</b> and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound <b>NK3</b> displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound <b>NK3</b> exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.