Synthesis and in vivo antitumor evaluation of an orally active potent phosphonamidate derivative targeting IDO1/IDO2/TDO.

Targeting Trp-Kyn pathways has been identified as an attractive approach for the cancer immunotherapies. In this study, a novel phosphonamidate containing compound was designed, synthesized and evaluated for its inhibitory activity against key dioxygenases in Trp-Kyn pathway, including IDO1, IDO2 and TDO. This compound showed potent IDO1 inhibitory activity with an IC50 value of 94 nM in an enzymatic assay and 12.6 nM in HeLa cells. In addition, this compound showed promising IDO2 inhibition and TDO inhibition with IC50 values of 310 nM and 2.6 µM, respectively, in enzyme assay. Based on the promising enzyme inhibitory activity toward IDO/TDO, compound F04 was evaluated of its antitumor effects in two tumor models. Further evaluation of mechanism demonstrated compound F04 with the remarkable capacity of reducing kynurenine level in plasma/TME and restoring anti-tumor immune response. F04 could be further developed as a potential immunotherapeutic agent combined with immune checkpoint inhibitors or chemotherapeutic drugs for cancer treatment.