ALW-II-49-7 is a selective EphB2 kinase inhibitor with an IC50 value of 40nM[1]. ALW-II-49-7 is also characterized as a DDR1 inhibitor(IC50 =12.4nM) and a DDR2 inhibitor(IC50=18.6nM)[2]. EphB2 kinase, a receptor tyrosine kinase belonging to the Eph family, is involved in various cellular signal transduction processes, including cell migration, adhesion, differentiation and proliferation[3]. DDR1 and DDR2 are also receptor tyrosine kinases that are widely expressed on the cell surface, activate downstream signaling pathways by recognizing collagen in the extracellular matrix, and regulate cell adhesion, migration, proliferation, and differentiation[4]. ALW-II-49-7 is commonly used in research of cancer and fibrosis[5][6].
In vitro, ALW-II-49-7 (0.01-10μM; 1h) inhibit the activity of EphB2 kinase in U87 glioblastoma cells[1]. In HEK293T (293T) cells transfected with wild-type DDR2, ALW-II-49-7 (0.1-10μM; 16h) decreases DDR2 phosphorylation in a dose-dependent manner[2]. ALW-II-49-7(3μM; 24h) significantly inhibited DDR1 phosphorylation induced by collagen I and reduced the synthesis of collagen IV in HEK293 cell lines and DDR1 knockout mesangial cells[7].
References:
[1] Choi Y, Syeda F, Walker JR, et al. Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2009;19(15):4467-4470.
[2] Terai H, Tan L, Beauchamp EM, et al. Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer. ACS Chem Biol. 2015;10(12):2687-2696.
[3] Liu W, Yu C, Li J, Fang J. The Roles of EphB2 in Cancer. Front Cell Dev Biol. 2022;10:788587.
[4] Agarwal G, Smith AW, Jones B. Discoidin domain receptors: Micro insights into macro assemblies. Biochim Biophys Acta Mol Cell Res. 2019;1866(11):118496.
[5] Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10(3):165-180.
[6] Ling S, Kwak D, Kim KK. Inhibition of discoidin domain receptor 2 reveals kinase-dependent and kinase-independent functions in regulating fibroblast activity. Am J Physiol Lung Cell Mol Physiol. 2023;325(3):L342-L351.
[7] Jeffries DE, Borza CM, Blobaum AL, Pozzi A, Lindsley CW. Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy. ACS Med Chem Lett. 2019;11(1):29-33.
ALW-II-49-7是一种选择性的EphB2激酶抑制剂，其IC50值为40nM[1]。ALW-II-49-7也是DDR1抑制剂（IC50 = 12.4nM）和DDR2抑制剂 ( IC50 = 18.6nM)[2]。EphB2激酶是Eph家族的受体酪氨酸激酶，参与多种细胞信号转导过程，包括细胞迁移、黏附、分化和增殖[3]。DDR1和DDR2也是受体酪氨酸激酶，它们广泛表达在细胞表面，通过识别细胞外基质中的胶原蛋白激活下游信号通路，调节细胞黏附、迁移、增殖和分化[4]。ALW-II-49-7常用于癌症和纤维化的研究[5][6]。
在体外实验中，ALW-II-49-7（0.01-10μM；1小时）能够抑制U87胶质母细胞瘤细胞中EphB2激酶的活性[1]。在转染了野生型DDR2的HEK293T（293T）细胞中，ALW-II-49-7（0.1-10μM；16小时）以剂量依赖的方式降低DDR2的磷酸化水平[2]。在HEK293细胞和DDR1基因敲除系膜细胞中，ALW-II-49-7（3μM；24小时）显著抑制了胶原蛋白I诱导的DDR1磷酸化，并减少了胶原蛋白IV的合成[7]。