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Purity: ≥98%
PF-06840003 (also known as PF06840003; EOS200271) is a highly potent and selective, orally bioavailable IDO-1 inhibitor (IC50 of 0.15 μM) with anticancer activity. It is a tryptophan analog, noncompetitive, and non-heme-binding IDO1 inhibitor licensed by iTeos SA to Pfizer for clinical development. Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. PF-06840003 has favorable human pharmacokinetic characteristics, a prolonged human half-life that may allow single-dose daily administration, and CNS penetration. PF-0684000 has moderate hIDO1 enzyme inhibition with IC50 0.41 μM. It is a highly efficient compound which is 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 |
PF-06840003 (EOS200271): Indoleamine 2,3-dioxygenase-1 (IDO-1) [1]
PF-06840003 (EOS200271): Indoleamine 2,3-dioxygenase-1 (IDO-1)exhibits good potency in human whole blood IDO-1 assay) [2] |
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| ln Vitro |
In vitro, PF-06840003 reverses T-cell anergy produced by IDO-1[1]. PF-06840003 exhibits action in both the LPS/INFγ-stimulated THP1 cells (IC50=1.7 μM) and the HeLa test (IC50=1.8 μM)[2].
1. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro, abrogating the immunosuppressive effect of IDO-1-mediated tryptophan catabolism on effector T-cells [1] 2. PF-06840003 showed good potency in a human whole blood IDO-1 assay, demonstrating effective inhibition of endogenous IDO-1 activity in a physiologically relevant in vitro system [2] 3. X-ray crystal structure analysis revealed that PF-06840003 binds to human IDO-1 with a novel mode, distinct from most reported IDO-1 inhibitors, as it does not interact with the heme iron atom of the enzyme [2] |
| ln Vivo |
When combined with immune checkpoint inhibitors, PF-06840003 decreases intratumoral kynurenine levels in mice by >80% and prevents tumor growth in several preclinical syngeneic models in mice. Positively anticipated human pharmacokinetic characteristics for PF-0684003 include a predicted t1/2 of 16–19 hours[1].
1. Oral administration of PF-06840003 reduced intratumoral kynurenine levels (a tryptophan catabolite) in mice by more than 80%, effectively blocking IDO-1-mediated tryptophan metabolism in the tumor microenvironment [1] 2. PF-06840003 inhibited tumor growth in multiple preclinical syngeneic mouse tumor models when combined with immune checkpoint inhibitors, showing synergistic in vivo efficacy in cancer immunotherapy [1] |
| Enzyme Assay |
1. To characterize the binding mode of PF-06840003 to human IDO-1, X-ray crystallography experiments were performed using the IDO-1 protein complexed with the drug; the crystal structure was resolved to analyze the spatial interaction between PF-06840003 and the IDO-1 active site, confirming its unique binding pattern that does not involve heme iron coordination [2]
2. A human whole blood IDO-1 activity assay was conducted to evaluate the potency of PF-06840003; whole blood samples were treated with varying concentrations of PF-06840003 and stimulated to induce IDO-1 expression, then the levels of tryptophan catabolites (kynurenine) were measured to determine the drug’s inhibitory effect on endogenous IDO-1 activity [2] |
| Cell Assay |
1. To assess the effect of PF-06840003 on IDO-1-induced T-cell anergy, in vitro cell co-culture models were established with IDO-1-expressing cells and effector T-cells; the cells were treated with PF-06840003, and T-cell proliferation, activation markers, and functional activity were measured to determine whether the drug reversed the anergic state of T-cells caused by IDO-1-mediated tryptophan depletion [1]
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| Animal Protocol |
p.o.
Mice 1. For in vivo efficacy evaluation, syngeneic tumor models were established in mice by implanting murine tumor cells into immunocompetent mice; PF-06840003 was administered orally (formulated as an oral bioavailable preparation) either as a monotherapy or in combination with immune checkpoint inhibitors, with dosing frequencies adjusted to maintain effective drug exposure [1] 2. Tumor growth was monitored regularly by measuring tumor volume over time to evaluate the antitumor efficacy of PF-06840003 combinations; at the end of the experiment, tumor tissues were collected, and intratumoral kynurenine levels were quantified using biochemical assays to assess the inhibition of IDO-1 activity in vivo [1] |
| ADME/Pharmacokinetics |
1. PF-06840003 is a small molecule with high oral bioavailability and good ADME properties, including good absorption and metabolic stability [1]. 2. The predicted human pharmacokinetic properties of PF-06840003 include a half-life (t1/2) of 16-19 hours, which supports reducing the frequency of administration in a clinical setting [1]. 3. PF-06840003 has shown very good ADME properties in preclinical studies, which contributes to its predicted good human pharmacokinetic properties [2].
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| References |
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| Additional Infomation |
The IDO1 inhibitor PF-06840003 is an orally potent hydroxyamidine compound that inhibits indoleamine 2,3-dioxygenase 1 (IDO1) and possesses potential immunomodulatory and antitumor activity. After administration, PF-06840003 targets and binds to IDO1, an enzyme responsible for oxidizing tryptophan to kynurenine. PF-06840003 increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T lymphocytes, by inhibiting IDO1 and reducing kynurenine levels in tumor cells. PF-06840003 also induces increased interferon (IFN) production and leads to a decrease in the number of tumor-associated regulatory T cells (Tregs). The immune system is suppressed in many cancers, and activation of the immune system can inhibit the growth of tumor cells expressing IDO1. IDO1 is a cytoplasmic enzyme responsible for the catabolism of tryptophan and its conversion to kynurenine. It is overexpressed in various tumor cell types and antigen-presenting cells (APCs); it plays a crucial role in immunosuppression. Tryptophan depletion inhibits the proliferation and activation of T lymphocytes, thereby suppressing the immune system.
1. Tumors utilize IDO-1 to break down tryptophan and accumulate kynurenine, inducing unresponsiveness in effector T cells and enhancing Treg cell function through FoxP3 upregulation; PF-06840003 targets this immunosuppressive pathway by inhibiting IDO-1 activity[1] 2. PF-06840003 is a highly selective IDO-1 inhibitor, being developed as a clinical candidate drug in immuno-oncology, with great potential for combination therapy with immune checkpoint inhibitors[1] 3. The chemical name of PF-06840003 (EOS200271) is 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; it was discovered from a high-throughput screening (HTS) lead compound (compound 5) and optimized to achieve highly efficient and selective IDO-1 inhibition[2] 4. PF-06840003 has a novel binding mode with human IDO-1, which distinguishes it from most other IDO-1 inhibitors that bind to heme iron atoms [2] |
| Molecular Formula |
C12H9FN2O2
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| Molecular Weight |
232.21
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| Exact Mass |
232.065
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| CAS # |
198474-05-4
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| Related CAS # |
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| PubChem CID |
23063810
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
1.713
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
17
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| Complexity |
360
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MXKLDYKORJEOPR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H9FN2O2/c13-6-1-2-10-7(3-6)9(5-14-10)8-4-11(16)15-12(8)17/h1-3,5,8,14H,4H2,(H,15,16,17)
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (10.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (10.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.3064 mL | 21.5322 mL | 43.0645 mL | |
| 5 mM | 0.8613 mL | 4.3064 mL | 8.6129 mL | |
| 10 mM | 0.4306 mL | 2.1532 mL | 4.3064 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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