914471-09-3

Basic information

• Product Name: indoleaMine-2,3-dioxygenase inhibitor INCB024360
• Synonyms: INCB 024360;INCB024360;INCB-024360;INCB-24360;indoleaMine-2,3-dioxygenase inhibitor INCB024360;INCB024360/INCB-024360;4-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide;(4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine
• CAS NO: 914471-09-3
• Molecular Formula: C₉H₇ClFN₅O₂
• Molecular Weight: 271.6355832
• Product Categories: Inhibitors
• Mol File: 914471-09-3.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 504.7±60.0 °C(Predicted)
• Appearance: /
• Density: 1.78±0.1 g/cm3(Predicted)
• Solubility: ≥13.55 mg/mL in DMSO
• PKA: 7.54±0.69(Predicted)
• CAS DataBase Reference: indoleaMine-2,3-dioxygenase inhibitor INCB024360(CAS DataBase Reference)
• NIST Chemistry Reference: indoleaMine-2,3-dioxygenase inhibitor INCB024360(914471-09-3)
• EPA Substance Registry System: indoleaMine-2,3-dioxygenase inhibitor INCB024360(914471-09-3)

Safety Data

• Hazardous Substances Data: 914471-09-3(Hazardous Substances Data)

Usage

Description

Indoleamine 2,3-dioxygenase inhibitor INCB024360, also known as Epacadostat, is a potent and selective inhibitor of indoleamine 2,3-dioxygenase (IDO1) with an IC50 of 10 nM. It shows high selectivity over other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO) and has been found to act as a competitive inhibitor of IDO1, demonstrating its effectiveness in mouse melanoma models.

Uses

Used in Oncology:
INCB024360 is used as an oncology agent for its potential role in modulating the immune response in cancer treatment. As a competitive inhibitor of IDO1, it can help counteract the immune tolerance that some tumors develop, thereby enhancing the effectiveness of immunotherapies and potentially improving patient outcomes.
Used in Drug Development:
INCB024360 is utilized in the development of new therapeutic strategies targeting IDO1, which is implicated in various pathological conditions, including cancer and autoimmune diseases. Its high selectivity and potency make it a valuable compound for research and development in the pharmaceutical industry.
Used in Preclinical Research:
In preclinical research, INCB024360 serves as a valuable tool for studying the role of IDO1 in disease progression and immune response. Its effectiveness in mouse melanoma models highlights its potential as a research compound for understanding the mechanisms of action and developing new treatment approaches for various cancers and related conditions.

In vitro

In IFN-γ–treated human HeLa cells, INCB024360 potently inhibits kynurenine production. INCB024360 also promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells.

In vivo

INCB024360 (100 mg/kg, p.o.), via IDO1 inhibition, suppresses kyn generation and tumor growth in immunocompetent, but not immunodeficient, mice. In mice bearing CT26 colon carcinoma, INCB024360 (100 mg/kg, p.o.) also inhibits the growth of IDO-expressing tumors by reducing kynurenine.

Biological Activity

incb024360 analogue is a potent and selective inhibitor of ido1 with ic50 value of 67 nm. [1]ido (indoleamine-pyrrole 2, 3-dioxygenase) is an enzyme which is encoded by the ido1 gene. ido is the rate-limiting and first enzyme of tryptophan which is one amino acid of human catabolism through kynurenine pathway. the decrease of l-tryptophan can cause halted growth of t cells as well as microbes. ido belongs to immunomodulatory enzyme. it is produced by some activated macrophages and immunoregulatory cells. ido is overexpressed in a wide range of cancer cells such as lung, prostatic, pancreatic, colorectal cancer. it is indentified to help cancer cells to escape the immune system by reducing the level of l-tryptophan in the microenvironment of cells.[2]in hela cells, incb024360 analogue selectively inhibited the activity of human ido1 with ic50 value of 19 nm. on the other hand, incb024360 analogue demonstrated little inhibition activity against tdo (tryptophan 2, 3-dioxygenase). in murine b16 cells, incb024360 analogue inhibited ido with ic50 value of 46 nm [1].in naive c57bl/6 mice, 100 mg/kg incb024360 analogue injected subcutaneously reduced kynurenine levels by >50% via inhibition of ido activity. in c57bl/6 mice bearing gm-csf- secreting b16 tumors, incb024360 analogue (25, 50, and 75 mg/kg b.i.d.) injected subcutaneously for 14 days dose-dependently inhibited tumor growth [1].

references

[1]. yue ew1, douty b, wayland b, et al. discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. j med chem. 2009 dec 10;52(23):7364-7.[2]. uyttenhove c, pilotte l, theate i, stroobant v, colau d, parmentier n, boon t, van den eynde bj: evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. nat med 2003, 9(10):1269-1274.

Upstream product

• 367-21-5 3-chloro-4-fluorophenylamine 
• 147085-13-0 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidamidoyl chloride 
• 372-19-0 meta-fluoroaniline 

Downstream Products

• 1204669-80-6 4-(3-chloro-4-fluorophenyl)-3-[(4-amino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one 
• 1204669-41-9 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-chloro-4-fluorophenyl)-N’-hydroxy-1,2,5-oxadiazole-3-carboximidamide 
• 1204669-81-7 N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide 
• 1204669-82-8 4-(3-chloro-4-fluorophenyl)-3-(4-{[2-(tritylamino)ethyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 
• 1204669-84-0 N-[2-({4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide 
• 1204669-83-9 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride 
• 1204669-86-2 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate 

Relevant articles and documents

Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer

Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10–21 nM, hIDO1 IC50 = 78–121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.

SUBSTITUTED N-HYDROXYAMIDINOHETEROCYCLES AS MODULATORS OF INDOLEAMINE 2,3- DIOXYGENASE

The invention provides modulators of indoleamine 2,3-dioxygenase (IDO1) and their use in the prophylaxis and/or treatment of IDO1-mediated diseases. Specifically, the present invention provides compounds according to Formula (I) an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.

Synthesis of [18F] 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L): A novel potential PET probe for imaging of IDO1 expression

To synthesize 18F-labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting 18F into a target molecule are necessary. The 18F-fluorobenzene moiety has been widely utilized in the synthesis of 18F-labeled compounds. The present study utilized [18F]-labeled aniline as intermediate in [18F]-radiolabeling chemistry for the facile radiosynthesis of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide ([18F]IDO5L) as indoleamine 2,3-dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC50. [18F]IDO5L was synthesized via coupling [18F]3-chloro-4-fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [18F]IDO5L was obtained with specific radioactivity ranging from 11 to 15GBq/μmol at the end of synthesis within ～90min, and the decay-corrected radiochemical yield was 18.2±2.1% (n=4).