生物活性

• 描述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. Epacadostat is a selective IDO1 inhibitor with IC50 value of ~10nM with little activity against the related enzymes IDO2 or TDO. Treatment with INCB024360 at concentration ranging in 1nM-1000nM for 2 days dose-dependently inhibit the kynurenine production in HeLa cells induced IDO1 production by IFN-γ, but did not affect the protein level of IDO1. Dose-dependent reverse of the suppression on T-cell proliferation by co-culture of HeLa^IDO1+/ DCs^IDO1+ in the presence of a soluble anti-CD3 antibody and human recombinant IL-2/ IFN-γ, LPS, or PGN can be observed by addition of Epacadostat at concentration ranging in 3-2000nM for 2 days. This reverse can also be observed in CD4⁺T cells, CD8⁺T cells, and NK cells treated with Epacadostat in the presence of DC^IDO1+ cells. Also addition of Epacadostat at 1μM for 6 days could reduce the conversion of naive CD4⁺CD25^- T cells to regulatory T cells induced by cocultured DC^IDO1+ cells, which is associated with tumor growth while regulatory T cells depletion enhances antitumor immune responses. Oral administration of Epacadostat at 25mg/kg or 100mg/kg twice a day can reduced tumor growth by 37% and 57% in female C57BL/6 mice bearing PAN02 pancreatic cancer cells and this was lymphocyte-dependent^[1].
• 作用机制INCB024360 is a reversible and competitive inhibitor of IDO1, but not a substrate of the IDO1 enzyme.^[1]

• 动物研究
  剂量	Mice: min = 10 mg/kg[2] (p.o.), max = 600 mg/kg[3] (p.o.); 2 mg/kg[2] (i.v.); 80 mg/kg[4] (i.p.)
  给药途径	p.o., i.v., i.p.
  动物药代数据	Animal Mice[2] Dose 2 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v., p.o. F 79.1% (p.o.) Vd 8.54 L/Kg (i.v.) T1/2 4.07 h (i.v.) 9.28 h (p.o.) Tmax 2 h (p.o.) CL 40.0 ml/min/kg (i.v.) Cmax 332 ng/ml (p.o.) AUC0→∞ 833 ng·h/ml (i.v.) 3292 ng·h/ml (p.o.)