Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3

Indoleamine-2,3-dioxygenase
1 (IDO1) and signal transducer and activator of transcription 3 (STAT3)
are important targets in the tumor microenvironment for cancer therapy.
In the present study, a set of naphthoquinone aromatic amide-oxime
derivatives were designed, which stimulated the immune response via
IDO1 inhibition and simultaneously displayed powerful antitumor activity
against three selected cancer cell lines through suppressing STAT3
signaling. The representative compound 8u bound effectively
to IDO1, with greater inhibitory activity relative to the commercial
IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear
translocation of STAT3. Consistently, in vivo assays demonstrated
a higher antiproliferative activity of compound 8u in
both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft
model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound
with dual immunotherapeutic and anticancer efficacy may represent
a new generation of highly efficacious drug candidates for cancer
therapy.