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: 198474-05-4

Selleck's PF-06840003 has been cited by 5 publications

Purity & Quality Control

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

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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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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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