Description:
IC50: 150, 220, and 70 nM for hJNK1, hJNK2, and hJNK3, respectively
Recent evidence suggests activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Therefore, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. AS601245 is a c-Jun NH2-terminal protein kinase inhibitor.
In vitro: AS601245 demonstrated a nonspecific inhibition of the three JNK human isoforms. AS601245 inhibits isolated hJNK3 in an ATPcompetitive manner. Selectivity of AS601245 was tested against a large panel of kinases. It exhibited 10- to 20-fold selectivity over c-src, CDK2, and c-Raf and more than 50- to 100-fold selectivity over a range of Tyr- and Ser/Thr-protein kinases [1].
In vivo: AS601245 administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and thus by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection or as i.v. bolus followed by an i.v. infusion was also observed in rats after focal cerebral ischemia [1].
Clinical trial: Up to now, AS601245 is still in the preclinical development stage.
Reference:
[1] Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA. AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther. 2004 Jul;310(1):25-32. Epub 2004 Feb 26.