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

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy. Herein, we describe the discovery of compound <b>4t</b>, the first inhibitor targeting both IDO1/2 that has excellent <i>in vitro</i> inhibitory activity (IDO1 IC₅₀ = 28 nM and IDO2 IC₅₀ = 144 nM). Notably, <b>4t</b> (TGI = 69.7%) exhibited significantly stronger <i>in vivo</i> antitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studies <i>in vivo</i> further identified that <b>4t</b> exerts its antitumor effect by inhibiting IDO1/2.