AG-1478 (Tyrphostin AG-1478, NSC 693255) is a selectiveEGFRinhibitor withIC50of 3 nM in cell-free assays, almost no activity on HER2-Neu, PDGFR, Trk, Bcr-Abl and InsR. AG-1478 (Tyrphostin AG-1478) inhibitsencephalomyocarditis virus (EMCV)andhepatitis c vi In vitro
AG-1478 is high selective over ErbB2 and PDGFR with IC50 of >100 μM. AG-1478 preferentially inhibits U87MG cells expressing truncated EGFR with IC50 of 8.7 μM, compared to those expressing endogenous wt EGFR or overexpressing exogenous wt EGFR with IC50 of 34.6 μM and 48.4 μM, respectively, and inhibits the DNA synthesis with IC50 of 4.6 μM, 19.67 μM, and 35.2 μM, respectively. AG-1478 also preferentially inhibits the tyrosine kinase activity and autophosphorylation of the ΔEGFR compared to endogenous or overexpressed exogenous wt EGFR. AG-1478 (0.25 μM) abolishes the MAPK activation induced by Ang II, a Ca2+ ionophore as well as EGF but not by a phorbol ester or platelet-derived growth factor-BB in the VSMC. AG-1478 inhibits EGF-induced mitogenesis of the BaF/ERX and LIM1215 cells with IC50 of 0.07 μM and 0.2 μM, respectively. AG1478 is able to inhibit the function of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2, with a more pronounced effect on ABCG2.
In vivo
Administration of AG-1478 blocks phosphorylation of the EGFR at the tumor site and inhibits the growth of A431 xenografts that overexpress the WT EGFR and glioma xenografts expressing the de2-7 EGFR. Even subtherapeutic doses of AG-1478 significantly enhance the efficacy of cytotoxic drugs, with the combination of AG-1478 and temozolomide displaying synergistic antitumor activity against human glioma xenografts. The combination of AG-1478 and an anti-EGFR antibody (mAb 806) displays additive and in some cases synergistic, antitumor activity against tumor xenografts overexpressing the EGFR. The combination of AG-1478 (0.4 mg) with a single dose of 25 μCi 90Y-CHX-A\'\'-DTPA-hu3S193 results in a significant enhancement of efficacy compared with either agent alone. Cell Data
cell lines：
Concentrations：Dissolved in DMSO, final concentrations ~100 μM
