Home Metabolism IDO/TDO inhibitor PF-06840003 For research use only.

PF-06840003

Synonyms: EOS200271

PF-06840003 (EOS200271) is a highly selective orally bioavailable IDO-1 inhibitor. Although it has moderate hIDO1 enzyme inhibition (IC50 0.41 μM), it is a highly efficient compound (LE 0.53, LipE 5.1), driven by its tight packing within the enzyme, as well as the high density of hydrogen bonds it forms with hIDO-1 despite its small size.

PF-06840003 Chemical Structure

PF-06840003 Chemical Structure

CAS No. 198474-05-4

Purity & Quality Control

Batch: S865701 DMSO]46 mg/mL]false]Ethanol]6 mg/mL]false]Water]Insoluble]false Purity: 99.97%
99.97

PF-06840003 Related Products

Biological Activity

Description PF-06840003 (EOS200271) is a highly selective orally bioavailable IDO-1 inhibitor. Although it has moderate hIDO1 enzyme inhibition (IC50 0.41 μM), it is a highly efficient compound (LE 0.53, LipE 5.1), driven by its tight packing within the enzyme, as well as the high density of hydrogen bonds it forms with hIDO-1 despite its small size.
Targets
hIDO-1 [1]
(Cell-free)		 dIDO-1 [1]
(Cell-free)		 mIDO-1 [1]
(Cell-free)
0.41 μM 0.59 μM 1.5 μM
In vitro
In vitro PF-06840003 is a racemic mixture. The IC50s of PF-06840003 for hIDO-1, mouse IDO-1 and dog IDO-1 are 0.41, 1.5 and 0.59 μM, respectively. It has very weak activity against hTDO-2, with an IC50 of 140 μM. In cellular assays, PF-06840003 shows activity both in the HeLa assay (IC50 1.8 μM) as well as in the LPS/INFγ-stimulated THP1 cells (IC50 1.7 μM). PF-06840003 is a very weak inhibitor of CYPs with IC50 values greater than 100 μM for most major CYP isozymes except 2C19 (IC50 value is 78 μM). Additionally, PF-06840003 does not exhibit metabolism-dependent (time-dependent and NADPH-dependent or time-dependent (NADPH-independent) inhibition of the major CYP enzymes investigated[1].
Cell Research Cell lines HeLa cervical carcinoma cells
Concentrations 0-50 μM
Incubation Time 16-24 h
Method

HeLa cells were harvested from cell culture flasks using 0.25% trypsin/EDTA and neutralized with EMEM growth medium. Following resuspension in fresh growth media, cells were seeded at 20,000 cells per well in 200 μL growth media in a 96-well plate and allowed to adhere at 37 °C at 5% CO2 overnight. The following day, growth media was aspirated and replaced with 200 μL of reduced (2%) serum media containing 100 ng/mL recombinant human interferon gamma (rhIFNγ) and incubated at 37 °C with 5% CO2 for 48 h to induce IDO-1 expression. On day four, compounds were diluted to 10 mM in DMSO and 11-point three-fold dilutions were prepared. rhIFNγ-containing media was removed, and following dilution into EMEM, compounds were added to cells at 50 μM top concentration and allowed to incubate 16−24 h at 37 °C with 5% CO2. On day five of the assay, 100 μL of cell supernatant was transferred to a v-bottom 96-well plate. Thirty microliters of 30% trichloroacetic acid (TCA) was added to each well to precipitate proteins, and plates were centrifuged at 3000 rpm for 10 min. One hundred microliters was transferred to a fresh flat-bottom 96-well plate, and 100 μL/well of 2% 4-(dimethylamino)benzaldehyde (pDMAB) in acetic acid was added to derivatize N-formyl kynurenine to kynurenine for quantitative colorimetric readout. Assay plates were read at A492 on Envision plate reader.
In Vivo
In vivo PF-06840003 has a predicted half-life of 16−19 h. Oral bioavailability in the mouse and rat was 59 and 94%, respectively, and 19% in dog. PF-06840003 has shown significant antitumor activity in monotherapy in Pan02, B16−F10, CT26, MC38, 4T1, and Renca models (p < 0.05 vs vehicle-treated group) and very good synergy in combination with anti-PDL1 mAb in CT26 model (p < 0.05 vs monotherapy groups).The PK profile of the compound is excellent, with a low/moderate clearance in most preclinical species. The compound also shows good CNS penetration in rat, suggesting potential impact on brain metastases[1].
Animal Research Animal Models CD-1 mice, Wistar−Han rat, and Beagle dog
Dosages 1 mg/kg (IV) and 3 mg/kg (oral)
Administration i.v./oral

Chemical Information & Solubility

Molecular Weight 232.21 Formula

C12H9FN2O2
 
CAS No. 198474-05-4 SDF Download PF-06840003 SDF
Smiles C1C(C(=O)NC1=O)C2=CNC3=C2C=C(C=C3)F
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 46 mg/mL ( (198.09 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 6 mg/mL

Water : Insoluble


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In vivo
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