JAK INHIBITOR I Chemical Properties

Melting point:

>178°C (dec.)

Boiling point:

646.5±55.0 °C(Predicted)

Density 

1.328

storage temp. 

-20C

solubility 

Soluble in DMSO (30 mg/ml)

form 

Off-white solid

pka

11.35±0.20(Predicted)

color 

Off-white

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

JAK INHIBITOR I Usage And Synthesis

Description

Pyridone 6 (457081-03-7) is a potent, ATP-competitive pan-JAK inhibitor. Inhibits 1, 2 and 3 (IC50=1, 5 and 15 nM respectively) as well as JAK family member Tyk2 (IC50=1 nM).1 Also tested against 21 other kinases with inhibition ranging from 130 nm to >10 mM. Inhibits IL2 and IL4-dependent proliferation of CTLL cells.1 Induces intermediate mesoderm differentiation from embryonic stem cells in a cocktail with LY-294002, CCG-1423 and retinoic acid.2 Potently inhibits STAT1, STAT5 and STAT6 phosphorylation and ameliorates allergic skin inflammation in a mouse model.3 Suppresses asthmatic responses in a mouse allergic asthma model.4

Uses

Pyridone 6 is a ATP-competitive JAK inhibitor in clinical development for the treatment of myeloproliferative neoplasms and B cell acute lymphoblastic leukemia.

Definition

ChEBI: 2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one is an organic heterotetracyclic compound that is 1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one bearing additional tert-butyl and fluoro substituents at positions 2 and 9 respectively. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor. It is an organic heterotetracyclic compound and an organofluorine compound.

in vivo

IC 50

JAK2: 1 nM (IC₅₀); Tyk2: 1 nM (IC₅₀); JAK3: 5 nM (IC₅₀); Murine JAK1: 15 nM (IC₅₀); CDK2: 3.3 μM (IC₅₀); cAMP-dependent kinase: 7.1 μM (IC₅₀); Csk: 2.1 μM (IC₅₀); Hck: 7.7 μM (IC₅₀); Fyn T: 0.5 μM (IC₅₀); p38: 11 μM (IC₅₀); MAPK: 1.78 μM (IC₅₀); Mek: 0.16 μM (IC₅₀); IκB Kinase 2: 0.3 μM (IC₅₀); KDR: 1.4 μM (IC₅₀); Flt-1: 1.52 μM (IC₅₀); Flt-4: 0.69 μM (IC₅₀); FGFR: 1.48 μM (IC₅₀); FGFR2: 0.94 μM (IC₅₀); Tek: 24 μM (IC₅₀); PDGFR: 1.49 μM (IC₅₀); PKC(α): 1.2 μM (IC₅₀)

storage

Store at -20°C

References

[1] JAMES E. THOMPSON. Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor[J]. Bioorganic & Medicinal Chemistry Letters, 2002, 12 8: Pages 1219-1223. DOI:10.1016/s0960-894x(02)00106-3
[2] SHIN-ICHI MAE . Combination of small molecules enhances differentiation of mouse embryonic stem cells into intermediate mesoderm through BMP7-positive cells[J]. Biochemical and biophysical research communications, 2010, 393 4: Pages 877-882. DOI:10.1016/j.bbrc.2010.02.111
[3] RYUSUKE NAKAGAWA. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17.[J]. ACS Applied Electronic Materials, 2011: 4611-4620. DOI:10.4049/jimmunol.1100649
[4] ATSUSHI MORIWAKI . IL-13 suppresses double-stranded RNA-induced IFN-λ production in lung cells[J]. Biochemical and biophysical research communications, 2011, 404 4: Pages 922-927. DOI:10.1016/j.bbrc.2010.12.082

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