PF-06840003

Investigational

Details

Stereochemistry	RACEMIC
Molecular Formula	C12H9FN2O2
Molecular Weight	232.2105
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CC2=C(NC=C2C3CC(=O)NC3=O)C=C1

InChI

InChIKey=MXKLDYKORJEOPR-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C12H9FN2O2
Molecular Weight	232.2105
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: http://cancerres.aacrjournals.org/content/76/14_Supplement/4863
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT02764151 | http://www.prweb.com/releases/2016/09/prweb13716749.htm

PF-06840003 is a highly selective orally bioavailable Indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor with a potent antineoplastic activity. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by >80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. A Phase 1 study of PF-06840003 in patients with Malignant Gliomas is ongoing.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Indoleamine 2,3-dioxygenase 19 Target ID: CHEMBL4685 Sources: http://cancerres.aacrjournals.org/content/76/14_Supplement/4863	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Malignant glioma 10 Sources: https://clinicaltrials.gov/ct2/show/NCT02764151	Primary	Phase I 428	Unknown Approved Use Unknown
Astrocytoma 3 Sources: https://clinicaltrials.gov/ct2/show/NCT02764151	Primary	Phase I 428	Unknown Approved Use Unknown
Oligodendroglioma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02764151	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
623 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
779.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
1763 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 2 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2474 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	500 mg 2 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
6115 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6680 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
12730 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 2 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
20410 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	500 mg 2 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
5.58 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
2.68 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	250 mg 2 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.885 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32436060/	500 mg 2 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PF-06840002 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852 inducer 97	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 BCRP 699 P-gp 1461 CYP1A2 1524	P-gp 1537 CYP1A2 1054	CYP1A2 701 CYPs 12

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	no
CYP2D6 1891	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	no
CYP3A4 1925	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	no
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 65.4 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 78 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 >100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 >100 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 >100 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak [IC50 >300 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak
CYPs 28	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	major
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/	weak

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/29111717/

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA002BG4	https://www.aablocks.com/goods/Goods/detail?id=AA002BG4
Aaron Chemicals	AR002C7W	http://www.aaronchem.com/198474-05-4
Aceschem	ACF023618	https://www.aceschem.com/catalog/198474-05-4.html
Ambeed	A196131	https://www.ambeed.com/products/198474-05-4.html
Ark Pharm	AK201382	http://www.arkpharminc.com/products/198474-05-4.html
AvaChem Scientific	6657	https://www.avachem.com/productSearch.asp?6657
Axon MedChem	3325	https://www.axonmedchem.com/product/3325
BLD Pharm	BD330724	http://www.bldpharm.com/products/198474-05-4.html
BOC Sciences	198474-05-4	https://www.bocsci.com/pf-06840003-cas-198474-05-4-item-7174.html
BioChemPartner	BCP17158	http://www.biochempartner.com/198474-05-4-BCP17158
CSNpharm	CSN16276	https://www.csnpharm.com/products/pf-06840003.html
Chem Scene	CS-6186	http://www.chemscene.com/198474-05-4.html
ChemShuttle	183261	http://www.chemshuttle.com/catalogsearch/result/?q=198474-05-4&cat=
ChemieTek	CT-PF0684	http://www.chemietek.com/pf-06840003-details.aspx
Chemspace	CSSB00025715390	https://chem-space.com/CSSB00025715390
Combi-Blocks	QM-8764	http://www.combi-blocks.com/cgi-bin/find.cgi?QM-8764
DC Chemicals	DC10022	http://www.dcchemicals.com/product_show-PF06840003.html
Excenen	EX-A1186	http://www.excenen.com/searchresultlist.php?id=198474-05-4
MedChem Express	HY-101111	https://www.medchemexpress.com/PF-06840003.html
MolPort	MolPort-042-681-295	https://www.molport.com/shop/molecule-link/MolPort-042-681-295
Selleck Chemicals	S8657	http://www.selleckchem.com/products/pf-06840003.html
Smolecule	S539217	http://www.smolecule.com/products/s539217
Smolecule	S806959	https://www.smolecule.com/products/s806959
Synblock Inc	SB22834	http://www.synblock.com/product/198474-05-4.html
THE BioTek	bt-279258	https://www.thebiotek.com/product/inhibitors/bt-279258
abcr GmbH	AB485583	http://www.abcr.com/shop/en/AB485583
eNovation Chemicals	D545579	http://www.enovationchem.com/productDetails.asp?productID=D545579
eNovation Chemicals	D573555	https://www.enovationchem.com/ProductDetails.asp?ProductID=D573555

Patents

Sample Use Guides

In Vivo Use Guide

600 mg/kg two times a day.

Route of Administration: Oral

In Vitro Use Guide

The assay was performed in 96-well flat bottom plates seeded with P815 cells overexpressing hlDO1 at a concentration of 2 χ 10^5 cells/well in a final volume of 200 μΙ. To determine IDO1 activity, the cells were incubated 24 hours at 37 °C at 5% C02 in IMDM (Invitrogen) supplemented with 2% FBS and 2% penicillin/streptomycin in the presence of the compounds (Compound 1, PF-06840003) of the present invention, at different concentrations. The plates were then centrifuged 5 min at 1000 rpm, and 100 μΙ of the supernatant were collected in a conical plate, 30 uL of TCA 30% were added and a further centrifugated at 3000 x g for 1 0 minutes. 100 μΙ of the supernatant were collected in a flat bottomed plate and 1 00 μΙ of 2% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenine concentrations were determined by measuring the absorbance at 480 nm.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 11:39:15 GMT 2023` Edited by `admin` on `Sat Dec 16 11:39:15 GMT 2023`
Record UNII	5K1FUI0T2C
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PF-06840003

Code

English

3-(5-FLUORO-1H-INDOL-3-YL)PYRROLIDINE-2,5-DIONE

Systematic Name

English

2,5-PYRROLIDINEDIONE, 3-(5-FLUORO-1H-INDOL-3-YL)-

Systematic Name

English

Code System Code Type Description

FDA UNII

5K1FUI0T2C