AG-18 (Tyrphostin 23) is a cell-permeable tyrosine kinase and epidermal growth factor receptor (EGFR) inhibitor, with an IC50 of 35μM for EGFR[1]. AG-18 blocks receptor autophosphorylation and activation of downstream signaling pathways by acting on the ATP-binding site or substrate-binding site of EGFR[2]. AG-18 is commonly applied to study EGFR-mediated signal transduction, regulation of cell proliferation, and receptor tyrosine kinase-related mechanisms[3,4].
In vitro, treatment of primary rat astrocytes with AG-18 (100μM) for 2h significantly increased lactate release and glucose consumption to 220% and 260% of the control, respectively[5]. Pretreatment of human alveolar epithelial A549 cells with AG-18 (30, 100, 300μM) for 30min, followed by continued treatment with TNF-α (10ng/mL) for 4.5h, dose-dependently inhibited TNF-α-induced surface expression of intercellular adhesion molecule-1 (ICAM-1)[6]. Co-incubation of AG-18 (25-200μM) with mouse striatal homogenate at 30℃ for 2min, using 10nM [3H]dopamine as the substrate, concentration-dependently inhibited dopamine uptake[7].
In vivo, LKB1null LUAD organoids were subcutaneously injected into NOD-SCID mice, and after palpable tumors formed, oral administration of AG-18 (100mg/kg; once daily) for 14 days significantly reduced tumor volume (by approximately 60-70%)[8].
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[3] Breen M E, Soellner M B. Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges[J]. ACS chemical biology, 2015, 10(1): 175-189.
[4] Hohnholt M C, Blumrich E M, Waagepetersen H S, et al. The tricarboxylic acid cycle activity in cultured primary astrocytes is strongly accelerated by the protein tyrosine kinase inhibitor tyrphostin 23[J]. Neurochemistry international, 2017, 102: 13-21.
[5] Blumrich E M, Kadam R, Dringen R. The protein tyrosine kinase inhibitor tyrphostin 23 strongly accelerates glycolytic lactate production in cultured primary astrocytes[J]. Neurochemical research, 2016, 41(10): 2607-2618.
[6] Chen C C, Chou C Y, Sun Y T, et al. Tumor necrosis factor α-induced activation of downstream NF-κB site of the promoter mediates epithelial ICAM-1 expression and monocyte adhesion: involvement of PKCα, tyrosine kinase, and IKK2, but not MAPKs, pathway[J]. Cellular Signalling, 2001, 13(8): 543-553.
[7] Simon J R, Bare D J, Ghetti B, et al. A possible role for tyrosine kinases in the regulation of the neuronal dopamine transporter in mouse striatum[J]. Neuroscience letters, 1997, 224(3): 201-205.
[8] Angelopoulou A, Theocharous G, Valakos D, et al. Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy[J]. Molecular Cancer, 2024, 23(1): 147.