product name JNK-IN-8
Description: JNK-IN-8, also known as JNK Inhibitor XVI, is the first irreversible and selective JNK inhibitor for JNK1, JNK2 and JNK4 with IC50 of 4.7 nM, 18.7 nM and 1 nM. JNK-IN-8 inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. JNK-IN-8 will be broadly useful as a pharmacological probe of JNK-dependent signal transduction.
References: Chem Biol. 2012 Jan 27;19(1):140-54; Biochem J. 2012 Jan 1;441(1):339-46; Chem Biol. 2013 Feb 21;20(2):146-59.
507.59
Formula
C29H29N7O2
CAS No.
1410880-22-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 100 mg/mL (197.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: JNK-IN-8 inhibits c-Jun phosphorylation in HeLa and A375 cells with EC50 of 486 nM and 338 nM, respectively. JNK-IN-8 shows a dramatic improvement in selectivity and eliminated binding to IRAK1, PIK3C3, PIP4K2C, and PIP5K3. JNK-IN-8 requires Cys116 for JNK2 inhibition. JNK-IN-8 (10 mM) suppresses the IL-1β-stimulated phosphorylation of c-Jun in IL-1R cells, an established substrate of the JNKs. JNK-IN-8 covalently attaches to the JNK isoforms caused a small retardation in the electrophoretic mobility of the JNK isoforms. JNK-IN-8 is discovered to inhibit JNK kinase by broad-based kinase selectivity profiling of a library of acrylamide kinase inhibitors based on the structure of imatinib using the KinomeScan approach. JNK-IN-8 possesses distinct regiochemistry of the 1,4-dianiline and 1,3-aminobenzoic acid substructures relative to imatinib and uses an N,N-dimethyl butenoic acetamide warhead to covalently target Cys154. JNK-IN-8 adopts an L-shaped type I binding conformation to access Cys 154 located toward the lip of the ATP-binding site Kinase Assay: JNK-IN-8 is a JNK1/2/3 inhibitor with high specificity. When JNK-IN-8 was profiled with a panel of 400 kinases, it exhibited specific binding to JNK 1/2/3 but not to other kinases. Crystallization study also found that JNK-IN-8 forms covalent bonds with conserved cysteine residue of JNK 1/2/3, resulting in a conformational change of the activation loop that blocks the substrate binding, thereby inhibiting the activity of JNK 1/2/3. Cell Assay: In Hela cells and A375 cells, pretreatment of cells with JNK-IN-8 resulted in the inhibition of c-Jun which is a direct phosphorylation substrate of JNK 1/2/3, confirming the inhibitory action of JNK-IN-8 on JNK 1/2/3. In HEK293-ILR1 cells following stimulation by anisomycin, the JNK-IN-8 was observed to inhibit c-Jun but not MSK1 and p38, and the inhibition was not reversible by removing JNK-IN-8 from culture medium. Additionally, JNK-IN-8 only exhibited on-pathway inhibition of JNK signaling pathway, which can be monitored by the phosphorylation of c-Jun. |
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| In Vivo | |
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| Formulation & Dosage | |
| References | Chem Biol. 2012 Jan 27;19(1):140-54; Biochem J. 2012 Jan 1;441(1):339-46; Chem Biol. 2013 Feb 21;20(2):146-59. |
