NVP-AEW541

This compound is a potent inhibitor of IGF-1R with cellular activity. Even though the compound has been screened against only a small number of other kinases, it shows some off-target activity, at least in biochemical assays. This compound is orally bioavailable and has been employed in in vivo experiments. It's selectivity profile has not been broadly defined.

This probe is suggested to be selective ATP-competitive inhibitor of IGF-1R, and to the lesser extent IR. The original paper (Cancer Cell. 2004 Mar;5(3):231-9) reports a 150 nM IC₅₀ for IGF-1R and 140 nM IC₅₀ for IR in vitro. In cell based assays that monitor autophosphorylation of IGF-1R and IR, the compound is more selective for IGF-1R (IC₅₀ 86 nM for IGF-1R and 2300 nM for IR). Based on in vitro biochemical assays compound potently inhibit kinase TEK, FLT-1, and FLT-3. Since kinome-wide selectivity of the probe was not evaluated, it can potentially inhibit other kinases in cells. The second paper (Cancer Res. 2005 May 1;65(9):3868-76); however, shows the correlation between the sensitivity of Ewing's Sarcoma, osteosarcoma and rhabdomyosarcoma cells to NVP-AEW541. This suggests that the compound had a major effect in those cell lines due to the inhibition of IGF-1R. Users should always confirm that NVP-AEW541 does not inhibit AKT phosphorylation upon EGF stimulation and does not inhibit IR autophosphorylation, to confirm selectivity. The original paper reports the inhibition of IGF-1R phosphorylation in vivo; however, data to confirm selectivity at the doses used were not provided. NVP-AEW541 is a potent inhibitor of IGF-1R and is useful for biochemical, cellular and in vivo studies. I recommend it for use with the caveat that its characterization is incomplete. It was reported prior to the availability of methods for the broad evaluation of kinase activity, and there is some degree of off-target activity even in the narrower characterization it has received.