LM10 is a selective tryptophan 2,3-dioxygenase (TDO) inhibitor with IC50 values of 0.62 and 2 μM for human and mouse TDO, respectively.
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Tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the enzymes controlling the rate-limiting step of the catabolism of tryptophan to immunosuppressive and neuroactive kynurenines, a key metabolic pathway regulating immune responses and neurotoxicity . LM10 can selective inhibit human and mouse TDO with IC50 values of 0.62 and 2 μM, respectively, which display good TDO inhibition with Ki of 5.5 μM. LM10 with a concentration of 1 mg/mL dissolved was given ad libitum to DBA/2 mice in the drinking water of 4 mL/mice/day, plasma concentration was detected from 60-136μM, suggesting a higher oral bioavailability. LM10 was also proved to be highly selective for TDO as, at 10 μM, none of the investigated systems are significantly inhibited. Furthermore, LM10 does not display any inhibitory potency on IDO at all. In an In vivo efficacy study, treatment of immunized mice with LM10 at 160 (mg/kg)/day prevented the growth of TDO-expressing P815 tumor cells . LM10 also showed no obvious signs of toxicity after more than 100 days of systemic administration of LM10 and no significant difference between treated and untreated mice for their plasma level of ALAP, γ-GT, ALAT and ASAT, all of which remained within the normal range. To determine whether the antitumor effects of LM10 resulted only from promoting tumor rejection or whether LM10 also had a direct effect on tumor cells, immunodeficient RAG2 knockout mice with TDO-expressing P815 cells was treated with LM10, while tumor growth was not affected by LM10 treatment indicating that the effect of LM10 was dependent on the immune system in this model.
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