Pyridone 6 displays potent inhibitory activity against JAK1 (IC50 = 15 nM for murine JAK1), JAK2 (IC50 = 1 nM), JAK3 (Ki = 5 nM), and Tyk2 (IC50 = 1 nM). JAK1 (Janus kinase 1), JAK2 and JAK3 belong to the family of non-receptor janus tyrosine kinases, which regulate a spectrum of cellular functions downstream of activated cytokine receptors in the lympho-hematopoietic system. Immunological stimuli, such as interferons and cytokines, induce recruitment of STAT transcription factors to cytokine receptor-associated JAK1, JAK2 and JAK3. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 5 mg/mL|
Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17.
Nakagawa R, et al. J Immunol. 2011 Nov 1;187(9):4611-20. PMID: 21957150.
Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma.
Matsunaga Y, et al. Biochem Biophys Res Commun. 2011 Jan 7;404(1):261-7. PMID: 21111712.
Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6.
Chrencik JE, et al. J Mol Biol. 2010 Jul 16;400(3):413-33. PMID: 20478313.
|Related JAK Products|
Peficitinib (ASP015K, JNJ-54781532) is an orally bioavailable JAK inhibitor, with IC50s of 3.9, 5.0, 0.7 and 4.8 nM for JAK1, JAK2, JAK3 and Tyk2, respectively.
FLLL32 is a potent JAK2/STAT3 inhibitor with IC50 of <5 μM.
WHI-P97 is a JAK3 inhibitor with an estimated Ki value of 0.09 microM from modeling studies and a measured IC50 value of 2.5 microM in EGFR kinase inhibition assays.
SAR-20347 is a potent dual inhibitor of JAK1 and TYK2 with IC50 values of 23 and 0.6 nM, respectively.
Itacitinib, also known as INCB39110 or INCB039110, is a potent JAK1 tyrosine kinase inhibitor.
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