BMK1 (Big MAP Kinase 1) is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. BMK1 is specifically activated by mitogen-activated protein kinase kinase 5 (MAP2K5/MEK5). It is involved in the downstream signaling processes of various receptor molecules including receptor type kinases, and G protein-coupled receptors. In response to extracelluar signals, this kinase translocates to cell nucleus, where it regulates gene expression by phosphorylating, and activating different transcription factors[3].
XMD8-92 is a BMK1 inhibitor. The dissociation constant (Kd) of XMD8-92 towards BMK1 was 80 nM, and data of XMD8-92 against other kinases suggested selectivity of XMD8-92 to BMK1. In a kinase activity assay utilizing Hela cell lysates, the IC50 of XMD8-92 against BMK1 was 1.5 μM. Furthermore, growth factor-induced activation of cellular BMK1 was effectively blocked by 1 μM XMD8-92, detected by mobility retardation. Cell proliferation assay revealed that 5 μM XMD8-92 inhibited more than 50% PC3, Hela and LL/2 cell growth when incubated for 48h[4]. 48h treatment of 25 μM XMD8-92 also inhibited cell proliferation of pancreatic tumor AsPC-1cells to the extent of more than 50%[5].
In animal experiments, treatment of mice bearing Hela or LL/2 xenografts with XMD8-92 at the dose of 50 mg/kg twice daily 1 day, several days, or weeks after inoculation of the tumor cells all significantly inhibit the growth of the tumors[4]. In an AsPC-1 xenograft model established in NOD/SCID mice, XMD8-92 administrated at the dose of 50 mg/kg i.p. daily for 15 days significantly inhibited tumor growth[5].
作用机制
XMD8-92 inhibits BMK1 via ATP site competition-binding. The selective binding and inhibition of XMD8-92 towards BMK1 was revealed by ATP-site competition binding assay and KiNativ method utilizing Hela cell lysates[4].
XMD8-92 细胞研究
细胞系
浓度
检测类型
检测时间
活性说明
数据源
human HeLa cells
Function assay
Inhibition of EGF-induced BMK1 autophosphorylation in human HeLa cells by SDS-PAGE analysis, IC50=0.24 μM
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