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. PF-06840003 is a selective IDO1 inhibitor with IC50 values of 0.41μM, 0.59μM and 1.5μM for hIDO-1, dIDO-1 and mIDO-1 (measured by enzymic acitivity), respectively. PF-06840003 is a racemic mixture, of which only the R-isomer is active, in development due to rapid epimerization of the chiral carbon that is adjacent to a carbonyl group. Incubation with PF-06840003 for 24h also showed significant inhibition on kynurenine production in HeLa, THP and human whole blood cells induced by INFγ or LPS[1], and reversed intratumoral KYN levels by >80% in vivo[2]. Oral administration of the PF-06840003 achieved total brain to plasma Kp ratio 0.51, indicating the brain penetrance of this compound[1]. Combination of PF-06840003 with immunotherapies including antibodies against PD-1 showed inhibition of tumor growth in multiple mouse syngeneic models[2].
作用机制
PF-06840003 forms H-bond interaction with the propionate of the heme, not the heme iron atom, which is differently from most of the IDO-1 inhibitors described so far.[1]
PF-06840003 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human periodontal ligament cells (hPDLCs)
50 µM
5 days
To inhibit IDO-1 activity and investigate its effect on CD4+ T lymphocyte proliferation and cytokine production. Results showed that IDO-1 inhibition significantly reversed the suppressive effect of hPDLCs on CD4+ T lymphocyte proliferation and reduced the production of IL-10, IL-17A, and IL-6.
J Clin Periodontol. 2020 Jun;47(6):689-701.
Hepa1–6
2 μM
48 hours
Inhibited IDO1 activity, reversed ZNF207-mediated CD8+ T cell exhaustion
J Immunother Cancer. 2022 Mar;10(3):e004414.
Human periodontal ligament stem cells (hPDLSCs)
50 µM
48 hours
Inhibition of IDO-1 enzymatic activity to evaluate its impact on the immunomodulatory function of hPDLSCs. Results showed that PF-06840003 significantly inhibited IDO-1 enzymatic activity.
Cells. 2020 May 14;9(5):1222.
PF-06840003 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Hepa1–6 subcutaneous xenograft tumor model
2 μM
PF-06840003 treatment reversed the tumor growth-promoting effect of ZNF207-OE
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