Discovery of the First Potent IDO1/IDO2 Dual Inhibitors: A Promising Strategy for Cancer Immunotherapy

Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactoryclinical efficacies of selective IDO1 inhibitors have impeded theirfurther development, suggesting that they do not exert sufficientantitumor effects by selectively inhibiting IDO1. IDO2, anisoenzyme of IDO1, is overexpressed in some human tumors,and emerging evidence suggests that concomitant inhibition ofIDO1/2 may have synergistic effects in cancer treatment, revealinga promising cancer immunotherapeutic strategy. Herein, wedescribe the discovery of compound4t, thefirst inhibitor targetingboth IDO1/2 that has excellentin vitroinhibitory activity (IDO1IC50= 28 nM and IDO2 IC50= 144 nM). Notably,4t(TGI =69.7%) exhibited significantly strongerin vivoantitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models,highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studiesin vivofurtheridentified that 4texerts its antitumor effect by inhibiting IDO1/2