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.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03707457	Glioblastoma ... more >>Glioblastoma Multiforme Collapse <<	Phase 1	Not yet recruiting	January 2024	-
  NCT03471286	Solid Tumor	Phase 1	Not yet recruiting	February 2023	United States, Maryland ... more >> Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, United States, 21231 Collapse <<
  NCT03589651	Unresectable or Metastatic Sol... more >>id Tumors Collapse <<	Phase 1	Recruiting	February 2022	United States, California ... more >> The Angeles Clinic (Cedars-Sinai) Not yet recruiting Los Angeles, California, United States, 90025 Principal Investigator: Ani Balmanoukian          United States, Illinois University of Chicago Medicine Not yet recruiting Chicago, Illinois, United States, 60637 Principal Investigator: Jason Luke          United States, North Carolina University of North Carolina Not yet recruiting Chapel Hill, North Carolina, United States, 27514 Principal Investigator: Juneko Grilley-Olson          United States, Pennsylvania University of Pennsylvania Not yet recruiting Philadelphia, Pennsylvania, United States, 19104 Principal Investigator: Greg Beatty          United States, Texas South Texas Accelerated Research Therapeutics Recruiting San Antonio, Texas, United States, 78229 Principal Investigator: Kyriakos Papadopolous          United States, Washington University of Washington, Seattle Cancer Care Not yet recruiting Seattle, Washington, United States, 98195 Principal Investigator: Gabi Chiorean          United Kingdom Royal Marsden Not yet recruiting London, United Kingdom, SW3 6JJ Principal Investigator: Udai Banerji Collapse <<

• 更多