AG-1478 is a selective EGFR tyrosine kinase inhibitor with IC50 of 3nM[1]. The transmembrane receptor tyrosine kinase (RTK) Epidermal Growth Factor Receptor (EGFR), a member of the ErbB family, orchestrates cell signaling, growth, differentiation, survival, and migration[2]. AG-1478, as an EGFR kinase inhibitor, is commonly used in research related to inflammation, cancer, and viral infections[3-5].
In vitro, treatment of MDA-MB-231 and MCF-7 cells with serial concentrations of AG-1478(5-40μM; 72h) suppressed cellular growth by inhibiting cell proliferation, inducing apoptosis, and inhibiting telomerase activity, while also significantly down-regulating the expression of MMP-9 and inhibiting cell invasion[6]. Treatment of Nasopharyngeal Carcinoma CNE2 cells with AG-1478(0-100μM; 72h) inhibited the proliferation of CNE2 cells by inhibiting EGFR phosphorylation and the activation of downstream molecules Akt and MAPK, inducing cell cycle arrest in G1 phase, and significantly up-regulating the levels of p27 protein[7].
In vivo, ApoE-/- mice were fed a high-fat diet (HFD) for 8 weeks, followed by oral administration of AG-1478 (10mg/kg/day) for 8 weeks significantly blocked the phosphorylation of cardiac EGFR induced by the high-fat diet, and reduced myocardial inflammation, fibrosis, apoptosis and dysfunction without affecting the levels of plasma low-density lipoprotein (LDL) and total triglycerides (TG) [8].
References:
[1] Bojko A, Reichert K, Adamczyk A, Ligęza J, Ligęza J, Klein A. The effect of tyrphostins AG494 and AG1478 on the autocrine growth regulation of A549 and DU145 cells. Folia Histochem Cytobiol. 2012;50(2):186-195.
[2] Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem. 2020;20(10):815-834.
[3] Shimizu S, Takezawa-Yasuoka K, Ogawa T, Tojima I, Kouzaki H, Shimizu T. The epidermal growth factor receptor inhibitor AG1478 inhibits eosinophilic inflammation in upper airways. Clin Immunol. 2018;188:1-6.
[4] Shushan A, Rojansky N, Laufer N, et al. The AG1478 tyrosine kinase inhibitor is an effective suppressor of leiomyoma cell growth. Hum Reprod. 2004;19(9):1957-1967.
[5] Dorobantu CM, Harak C, Klein R, et al. Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα. Antimicrob Agents Chemother. 2016;60(10):6402-6406.
[6] Zhang YG, Du Q, Fang WG, Jin ML, Tian XX. Tyrphostin AG1478 suppresses proliferation and invasion of human breast cancer cells. Int J Oncol. 2008;33(3):595-602.
[7] Zhu XF, Liu ZC, Xie BF, et al. EGFR tyrosine kinase inhibitor AG1478 inhibits cell proliferation and arrests cell cycle in nasopharyngeal carcinoma cells. Cancer Lett. 2001;169(1):27-32.
[8] Li W, Fang Q, Zhong P, et al. EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice. Sci Rep. 2016;6:24580.
AG-1478是一种选择性的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，其IC50值为3nM[1]。跨膜受体酪氨酸激酶（RTK）表皮生长因子受体（EGFR）是ErbB家族的一员，协调细胞信号传导、生长、分化、存活和迁移[2]。作为EGFR激酶抑制剂，AG-1478通常用于炎症、癌症和病毒感染等相关研究[3-5]。
在体外实验中，用不同浓度的AG-1478（5-40μM；72小时）处理MDA-MB-231和MCF-7细胞，可通过抑制细胞增殖、诱导细胞凋亡和抑制端粒酶活性来抑制细胞生长，同时显著下调MMP-9的表达并抑制细胞侵袭[6]。用AG-1478（0-100μM；72小时）处理鼻咽癌CNE2细胞，可通过抑制EGFR磷酸化及其下游分子Akt和MAPK的激活，诱导细胞周期停滞在G1期，并显著上调p27蛋白的水平，从而抑制CNE2细胞的增殖[7]。
在体内实验中，对ApoE-/-小鼠进行高脂饮食（HFD）喂养8周后，再给予AG-1478（10mg/kg/天）口服治疗8周，可显著阻断高脂饮食诱导的心脏EGFR磷酸化，并减少心肌炎症、纤维化、凋亡和功能障碍，而不影响血浆低密度脂蛋白（LDL）和总甘油三酯（TG）水平[8]。