AG-490

AG-490 (Tyrphostin AG 490) is a multi-targeted tyrphostin family of tyrosine kinase inhibitor, inhibits EGF receptor tyrosine kinase with IC50 of 2 and 13.5 uM for EGFR and ErbB2, also inhibits JAK2, JAK3/STAT, JAK3/AP-1 and JAK3/MAPK pathways; selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, blocks the constitutive activation of Stat3 and inhibits spontaneous as well as IL2-induced growth of MF tumor cells.Blood Cancer Discontinued(In Vitro):AG490 inhibits the activation of Stat-3 by selectively blocking JAK2. AG490 is used to selectively inhibit JAK/Stat-3 activation. At a dose of 10 μM, Stat-3 phosphorylation is decreased by >95% and cell viability is maintained. AG490 at a dose of 10 μM results in >95% decrease in pStat-3 in EGF-stimulated A431 cells with no effect on Stat-3 mass. AG-490 is a potent inhibitor of the JAK3/STAT, JAK3/AP-1, and JAK3/MAPK pathways and their cellular consequences. AG-490 abolishes IL-2-inducible [3H]thymidine incorporation in a dose-dependent manner, displaying an IC50 of 25 μM. AG-490 potently inhibits IL-2-mediated proliferation in T cells, results distinct from previous studies that showed this agent induced apoptosis in ALL cells while exerting apparently no effects on the growth of mitogen-stimulated normal T cells.(In Vivo):AG490 significantly inhibits the development of type 1 diabetes (T1D) (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 (1 mg/mouse) markedly results in disease remission in treated animals (n=23) in comparision to the absolute inability (0%; 0/10, p=0.003, Log-rank test) of DMSO and sustained eugluycemia is maintained for several months following drug withdrawal. AG490 (1-10 μg) significantly attenuates -carrageenan-induced thermal hyperalgesia in a dose-dependent manner. AG490 also reduces mechanical hyperalgesia.