INCB024360 analogue

IDO5L is a potent indoleamine 2,3-dioxygenase (IDO) inhibitor with an IC50 of 67 nM.

Signaling Pathways >> Metabolic Enzyme/Protease >> Indoleamine 2,3-Dioxygenase (IDO)

Research Areas >> Cancer

IDO:67 nM (IC50)

IDO:19 nM (IC50, in HeLa cell)

IDO5L (Compound 5l) is a potent (HeLa IC50=19 nM) inhibitor of IDO[1]. IDO5L is one of the highest potent inhibitors of the IDO1 (IC50=19 nM, in HeLa cell assay)[2].

Testing of IDO5L in mice demonstrates pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors. Initial oral pharmacokinetic studies show that IDO5L is rapidly cleared (t1/2<0.5 h) and that oral administration will not be a suitable dosing method for in vivo studies. The measured plasma exposure (2.5 μM) of IDO5L during this period exceeded our calculated mouse protein binding adjusted B16 cellular IC50 (PBadjIC50=1.0 μM, murine cellular B16 IC50=46 nM). Notably, kynurenine levels increase back to baseline after 4 h as IDO5L exposure levels decreased below the mouse PBadjIC50 from 1.0 to 0.1 μM[1].

Mice[1] A single subcutaneous 100 mg/kg dose of IDO5L is administered to naive C57BL/6 mice bearing GM-CSF-secreting B16 tumors. Blood is harvested from individual mice over 8 h. Kynurenine and IDO5L concentrations are measured by LCMS. Reductions of kynurenine levels by 50-60% are observed between 2 and 4 h, with maximum inhibition seen at 2.5 h. Tumors are allowed to grow until day 7 when 14 days of subcutaneous dosing of IDO5L at 25, 50, and 75 mg/kg b.i.d. is initiated. Dose dependent inhibition of tumor growth is correlated with increasing exposures of IDO5L in plasma.

[1]. Yue EW, et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem. 2009 Dec 10;52(23):7364-7.

[2]. Huang X, et al. Synthesis of [(18) F] 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression. J Labelled Comp Radiopharm. 2015 Apr;58(4):156-62.

Epacadostat(INCB024360) | Indoximod | Linrodostat (BMS-986205) | NLG919 | Coptisine chloride | Navoximod | PF-06840003 | GNF-PF-3777 | IDO-IN-4 | IDO-IN-1 | IDO-IN-12 | IDO-IN-2 | IDO-IN-3 | IDO-IN-11