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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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AG-1478 (Tyrphostin AG-1478) is a selective EGFR inhibitor with IC50 of 3 nM. |
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Targets
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EGFR |
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IC50 |
3 nM [1] |
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In Vitro
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AG-1478 is high selective over ErbB2 and PDGFR with IC50 of >100 μM. [1] 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. [2] 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. [3] AG-1478 inhibits EGF-induced mitogenesis of the BaF/ERX and LIM1215 cells with IC50 of 0.07 μM and 0.2 μM, respectively. [6] 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. [7] |
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In Vivo
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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. [4] 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. [5] |
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Clinical Trials
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Features
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Combination Therapy
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Description
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AG-1478 in combination with cisplatin displays significantly higher antitumor activity against established U87MG.Δ2-7 and A431 xenografts than either agent used alone. [4] Similar to erlotinib, AG-1478 potently sensitizes drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Furthermore, AG-1478 is able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wildtype or mutated ABCG2. [8] AG-1478 in combination with cisplatin or paclitaxel has a synergistic effect against endometrial and ovarian cancer cells. [9] |
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Protocol
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Cell Assay
[2]
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| Cell Lines |
U87MG |
| Concentrations |
Dissolved in DMSO, final concentrations ~100 μM |
| Incubation Time |
72 hours |
| Methods |
Cells are exposed to different concentrations of AG-1478 for 72 hours in 96-well plates. The effects of AG-1478 on cell growth are examined using an Alamar Blue assay. A 20-μL aliquot of Alamar Blue is added to each well, and its absorbance is determined using a Spectromax Scanning Micro plate Reader. The effects of AG-1478 are expressed as percentage of growth inhibition using untreated cells as the control (0% inhibition). Cellular DNA synthesis is determined using a [3H]thymidine incorporation assay. |
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Animal Study
[4]
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| Animal Models |
Female BALB/c nu/nu mice inoculated s.c. with A431 or U87MG.Δ2-7 tumor cells |
| Formulation |
Dissolved in 100 mM Captisol |
| Doses |
~1 mg/kg |
| Administration |
Injection i.p. three times per week |
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References |
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[1] Levitzki A, et al. Science, 1995, 267(5205), 1782-1788.
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[2] Han Y, et al. Cancer Res, 1996, 56(17), 3859-3861.
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[3] Eguchi S, et al. J Biol Chem, 1998, 273(15), 8890-8896.
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[4] Johns TG, et al. Proc Natl Acad Sci U S A, 2003, 100(26), 15871-15876.
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[5] Lee FT, et al. Clin Cancer Res, 2005, 11(19 Pt 2), 7080s-7086s.
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[6] Ellis AG, et al. Biochem Pharmacol, 2006, 71(10), 1422-1434.
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