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, 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 4t, the first inhibitor
targeting both IDO1/2 that has excellent in vitro inhibitory activity (IDO1 IC50 = 28 nM and IDO2 IC50 = 144 nM). Notably, 4t (TGI = 69.7%) exhibited
significantly stronger in vivo 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 in vivo further identified
that 4t exerts its antitumor effect by inhibiting IDO1/2.