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
Pyridone 6 (P6) delays the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6-nano strongly ameliorates atopic dermatitis (AD) in NC/Nga mice, exerting an effect comparable to that of betamethasone ointment, a commonly used drug, which also tested as a positive control. In contrast, empty polylactic acid with glycolic acid (PLGA) nanoparticles (C-nano) seemed to have no effect[2].
IC 50
JAK2: 1 nM (IC
50); Tyk2: 1 nM (IC
50); JAK3: 5 nM (IC
50); Murine JAK1: 15 nM (IC
50); CDK2: 3.3 μM (IC
50); cAMP-dependent kinase: 7.1 μM (IC
50); Csk: 2.1 μM (IC
50); Hck: 7.7 μM (IC
50); Fyn T: 0.5 μM (IC
50); p38: 11 μM (IC
50); MAPK: 1.78 μM (IC
50); Mek: 0.16 μM (IC
50); IκB Kinase 2: 0.3 μM (IC
50); KDR: 1.4 μM (IC
50); Flt-1: 1.52 μM (IC
50); Flt-4: 0.69 μM (IC
50); FGFR: 1.48 μM (IC
50); FGFR2: 0.94 μM (IC
50); Tek: 24 μM (IC
50); PDGFR: 1.49 μM (IC
50); PKC(α): 1.2 μM (IC
50)
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
