Description
c-Jun amino terminal kinases (JNKs) are MAP kinase family members that become highly activated after cells are exposed to stress conditions and are poorly activated by exposure to growth factors or mitogens. They have been implicated in neurodegeneration, rheumatoid arthritis, inflammation, cancer, and diabetes. JNK1 and JNK2 are widely expressed throughout the body whereas JNK3 is predominantly distributed in the brain. JNK Inhibitor VIII is an aminopyridine compound that inhibits JNK1, JNK2, and JNK3 with Ki values of 2, 4, and 52 nM, respectively. It has been reported to inhibit the phosphorylation of the JNK substrate c-Jun in HepG2 cells (EC50 = 920 nM) without affecting the expression of IL-6, IL-8, or COX-2.
Uses
JNK Inhibitor VIII is an inhibitor shown to suppress apoptosis, caspase cleavage, and cytochrome C release.
in vitro
cs jnk 6o, in a dose-dependent manner, inhibits phosphorylation of c-jun (ec50 = 920 nm) and prevents collagen-induced platelet aggregation. at low collagen concentrations (0.2 and 0.5 μg/ml), platelet aggregation was totally or partially impaired by 10 μm cs jnk 6o, whereas at a high collagen concentration (5 μg/ml), tcs jnk 6o had no effect [2].
in vivo
. pharmacokinetic profiles were studied for tcs jnk 6o in sprague-dawley rats. tcs jnk 6o showed a short half-life of about 1 hour, with barely measurable bioavailability and rapid clearance. microsomal incubation studies revealed that the oxidative metabolism of tcs jnk 6o was very rapid [1]
IC 50
45 nm for jnk1 and 160 nm for jnk2 [1]
References
[1] szczepankiewicz bg1, kosogof c, nelson lt, liu g, liu b, zhao h, serby md, xin z, liu m, gum rj, haasch dl, wang s, clampit je, johnson ef, lubben th, stashko ma, olejniczak et, sun c, dorwin sa, haskins k, abad-zapatero c, fry eh, hutchins cw, sham hl, rondinone cm, trevillyan jm. aminopyridine-based c-jun n-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. j med chem. 2006 jun 15;49(12):3563-80.
[2] kauskot a, adam f, mazharian a, ajzenberg n, berrou e, bonnefoy a, rosa jp, hoylaerts mf, bryckaert m. involvement of the mitogen-activated protein kinase c-jun nh2-terminal kinase 1 in thrombus formation. j biol chem. 2007 nov 2;282(44):31990-9.
