IDO1 (Indoleamine 2,3-dioxygenase-1) is a heme-containing monomeric oxidoreductase, which can catalyze the degradation of the essential amino acid tryptophan to N-formyl-kynurenine, an intermediate metabolized through a series of steps to form NAD+. IDO1 is considered to play an important role in the induction of tumor immune tolerance, which can regulate the immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. Indoximod is the D-isomer of 1-methyl-tryptophan which is the first IDO inhibitor with Ki value of 7-70μM[1]. The two stereoisomers, 1-methyl-D-Trp (Indoximod) and 1-methyl-L-Trp, possess potentially different biological properties. Compared with 1-methyl-L-Trp, Indoximod exhibited much less potency to IDO enzymic activity on kynurenine production in both purified enzyme and in HeLa cell–based (IC25>100μM) assays. However, Indoximod showed much significant effect on reversing the suppression of T cells created by DCsIDO1+ (dendritic cellsIDO1+), which suggesting that Indoximod may function more efficiently against immunosuppression. Consistent with this, an in vivo study showed that Indoximod (400 mg/kg by oral gavage twice daily, five times a week) was more efficacious as an anticancer agent dependent on IDO gene expression in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer, with combined treatment with chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine[2].
作用机制
Indoximod is an analogue of D-Trp, which works as a competitive inhibitor for indoleamine 2,3-dioxygenase.[1]
搜索
