Indoximod

Indoximod (NLG-8189, 1-Methyl-D-tryptophan, D-1MT) is a potent Indoleamine 2,3-dioxygenase (IDO) inhibitor with IC50 of 7 uM; prevents T-cell anergy triggered by dendritic cells overexpressing IDO in mice; augments the antitumor and antiviral immunoresponse of CD8+ T-cells and reduces tumor volume in mice with xenografts overexpressing IDO.Breast Cancer Phase 2 Clinical (In Vitro) :The IDO inhibitor 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties. The L isomer is the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell–based assays. However, the D isomer is significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells. The L isomer of 1-methyl-tryptophan functioned as a competitive inhibitor (Ki=19 μM), whereas the d isomer is much less effective. The DL mixture is intermediate, with a Ki of 35 μM. (In Vivo) :The D isomer is more efficacious as an anticancer agent in chemo-immunotherapy regimens using NSC-26271, NSC 125973, or LY 188011, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targets the IDO gene because the antitumor effect of d-1-methyl-tryptophan is completely lost in mice with a disruption of the IDO gene (IDO-knockout mice) . Oral administration of dl-1-methyl-tryptophan in combination with NSC 125973 can elicit regression of autochthonous breast tumors.