EOS200271 | PF-06840003 | CAS#198474-05-4 | IDO-1 inhibitor

MedKoo Cat#: 206931 | Name: PF-06840003

Description:

WARNING: This product is for research use only, not for human or veterinary use.

PF-06840003, also known as EOS200271, is potent IDO-1 inhibitor (IC50 0.15 μM). PF-0684000 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-0684000 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16−19 h.

Chemical Structure

PF-06840003

CAS#198474-05-4

Theoretical Analysis

MedKoo Cat#: 206931

Name: PF-06840003

CAS#: 198474-05-4

Chemical Formula: C12H9FN2O2

Exact Mass: 232.0648

Molecular Weight: 232.21

Elemental Analysis: C, 62.07; H, 3.91; F, 8.18; N, 12.06; O, 13.78

Price and Availability

Size	Price	Availability
25mg	USD 90.00	Ready to ship
50mg	USD 150.00	Ready to ship
100mg	USD 250.00	Ready to ship
200mg	USD 450.00	Ready to ship
500mg	USD 950.00	Ready to ship
1g	USD 1,550.00	Ready to ship
2g	USD 2,850.00	Ready to ship

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Related CAS #

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Synonym

EOS200271, EOS-200271; EOS 200271; PF-06840003; PF 06840003; PF06840003; PF-0684003; PF 0684003; PF0684003;

IUPAC/Chemical Name

3‑(5-Fluoro‑1H‑indol-3-yl)pyrrolidine-2,5-dione

InChi Key

MXKLDYKORJEOPR-UHFFFAOYSA-N

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)

SMILES Code

O=C(C(C1=CNC2=C1C=C(F)C=C2)C3)NC3=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

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. DO1 inhibitor PF-06840003 targets and binds to IDO1, an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, PF-06840003 increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T lymphocytes; PF-06840003 also induces increased interferon (IFN) production, and causes a reduction in tumor-associated regulatory T cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may inhibit the growth of IDO1-expressing tumor cells. IDO1, a cytosolic enzyme responsible for tryptophan catabolism and the conversion of tryptophan into kynurenine, is overexpressed by a variety of tumor cell types and antigen presenting cells (APCs); it plays an important role in immunosuppression. Tryptophan depletion inhibits T-lymphocyte proliferation and activation, and subsequently suppresses the immune system.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A9T11K10

QC Data

View QC data: current batch, Lot#A9T11K10

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

PF-06840003 (EOS200271) is an IDO-1 inhibitor with IC50s of 0.41 μM, 0.59 μM, and 1.5 μM for hIDO-1, dIDO-1, and mIDO-1, respectively.

In vitro activity:

In vitro coculture of IDO1-expressing SKOV3 tumor cells and T lymphocytes was established to mimic the physiologic consequences of IDO1 expression in the tumor microenvironment on T-cell proliferation. Reduced T-cell proliferation in the presence of IDO1-positive tumor cells is used as a surrogate for the contribution of IDO1 to T-cell anergy in the tumor microenvironment. PF-06840003 effectively rescued IDO1-induced T-cell anergy in this assay with an EC50 of 80 nmol/L (Table 1; Supplementary Fig. S2A–S2C). The ability of PF-06840003 to rescue T-cell proliferation appeared to be serum-independent with EC50 values from 60 to 74 nmol/L in serum concentrations ranging from 10% to 50%. Reference: Mol Cancer Ther. 2018 Dec;17(12):2530-2542. https://mct.aacrjournals.org/content/17/12/2530.long

In vivo activity:

PF-06840003 administration caused a significant dose-dependent decrease of plasma L-kynurenine levels (Fig. 1C). L-kynurenine reduction peaked at 1 hour post dose and correlated with concentrations of unbound active PF-06840002. A strong maximum reduction in plasma L-kynurenine (≥54 ± 6%) was observed at or above 200 mg/kg 1 hour after treatment. Based on the human whole blood assay and the 3.8-fold potency difference for inhibiting human versus mouse IDO1, the estimated in vivo IC50 and IC90 for free, unbound active PF-06840002 against mouse IDO1 are 4 μmol/L and 21 μmol/L, respectively. Plasma L-kynurenine largely returned to or exceeded control levels by 24 hours after PF-06840003 administration. Interestingly, maximally reduced L-kynurenine levels are comparable with the observed lower plasma concentrations in IDO1 knock-out mice. It was thus concluded that PF-06840003 can achieve transient complete inhibition of IDO1 catalytic activity in mice following oral administration. Reference: Mol Cancer Ther. 2018 Dec;17(12):2530-2542. https://mct.aacrjournals.org/content/17/12/2530.long

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	30.0	129.20

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 232.21 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, Dalvie D, Denies S, Dillon CP, Fantin VR, Guo J, Letellier MC, Li W, Maegley K, Marillier R, Miller N, Pirson R, Rabolli V, Ray C, Streiner N, Torti VR, Tsaparikos K, Van den Eynde BJ, Wythes M, Yao LC, Zheng X, Tumang J, Kraus M. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy. Mol Cancer Ther. 2018 Dec;17(12):2530-2542. doi: 10.1158/1535-7163.MCT-17-1104. Epub 2018 Sep 19. PMID: 30232146. 2. Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Négrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, Wythes M. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate. J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974. Epub 2017 Nov 21. PMID: 29111717. 3. Liu Y, Li S, Gao Z, Li S, Tan Q, Li Y, Wang D, Wang Q. Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism. Cardiovasc Toxicol. 2021 Aug;21(8):655-668. doi: 10.1007/s12012-021-09657-y. Epub 2021 May 21. PMID: 34021461; PMCID: PMC8211584.

In vitro protocol:

In vivo protocol:

1. Liu Y, Li S, Gao Z, Li S, Tan Q, Li Y, Wang D, Wang Q. Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism. Cardiovasc Toxicol. 2021 Aug;21(8):655-668. doi: 10.1007/s12012-021-09657-y. Epub 2021 May 21. PMID: 34021461; PMCID: PMC8211584. 2. Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, Dalvie D, Denies S, Dillon CP, Fantin VR, Guo J, Letellier MC, Li W, Maegley K, Marillier R, Miller N, Pirson R, Rabolli V, Ray C, Streiner N, Torti VR, Tsaparikos K, Van den Eynde BJ, Wythes M, Yao LC, Zheng X, Tumang J, Kraus M. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy. Mol Cancer Ther. 2018 Dec;17(12):2530-2542. doi: 10.1158/1535-7163.MCT-17-1104. Epub 2018 Sep 19. PMID: 30232146.

1: Sadek M, Stover KR, Liu X, Reed MA, Weaver DF, Reid AY. IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats. J Neurosci Res. 2024 May;102(5):e25338. doi: 10.1002/jnr.25338. PMID: 38706427. 2: Liu Y, Li S, Gao Z, Li S, Tan Q, Li Y, Wang D, Wang Q. Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR- Dependent Mechanism. Cardiovasc Toxicol. 2021 Aug;21(8):655-668. doi: 10.1007/s12012-021-09657-y. Epub 2021 May 21. Retraction in: Cardiovasc Toxicol. 2023 Feb;23(2):120. doi: 10.1007/s12012-023-09779-5. PMID: 34021461; PMCID: PMC8211584. 3: Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S, Williams JH, Li R, Taylor CT, Lassman AB. A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. Invest New Drugs. 2020 Dec;38(6):1784-1795. doi: 10.1007/s10637-020-00950-1. Epub 2020 May 20. PMID: 32436060. 4: Pham KN, Lewis-Ballester A, Yeh SR. Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. J Am Chem Soc. 2019 Nov 27;141(47):18771-18779. doi: 10.1021/jacs.9b08871. Epub 2019 Nov 14. PMID: 31682426; PMCID: PMC7366343. 5: Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, Dalvie D, Denies S, Dillon CP, Fantin VR, Guo J, Letellier MC, Li W, Maegley K, Marillier R, Miller N, Pirson R, Rabolli V, Ray C, Streiner N, Torti VR, Tsaparikos K, Van den Eynde BJ, Wythes M, Yao LC, Zheng X, Tumang J, Kraus M. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy. Mol Cancer Ther. 2018 Dec;17(12):2530-2542. doi: 10.1158/1535-7163.MCT-17-1104. Epub 2018 Sep 19. PMID: 30232146. 6: Cheong JE, Ekkati A, Sun L. A patent review of IDO1 inhibitors for cancer. Expert Opin Ther Pat. 2018 Apr;28(4):317-330. doi: 10.1080/13543776.2018.1441290. Epub 2018 Feb 23. PMID: 29473428. 7: Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Négrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, Wythes M. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate. J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974. Epub 2017 Nov 21. PMID: 29111717.