CGP 57380

CGP 57380 is a specific and selective inhibitor of MNK1 with IC50 value of 2.2 μM [1].

Mitogen-activated protein (MAP) kinase interacting kinases 1 (MNK1) is a serine/threonine kinase and is able to integrate signal from MAP kinase pathway and phosphorylate eIF4E [1].

CGP 57380 is a specific and selective MNK1 inhibitor. In 293 cells, CGP 57380 (10 μM) inhibited eIF4E phosphorylation in response to fetal calf serum (FCS), arsenite, anisomycin, PMA or tumor necrosis factor alpha. Also, CGP 57380 increased the cap-dependent reporter rluc. In cellular assays, CGP 57380 inhibited eIF4E phosphorylation with IC50 value of 3 μM [1]. In rat vascular smooth muscle cells, CGP 57380 inhibited eIF4E phosphorylation, protein synthesis and VSMC hypertrophy induced by angiotensin II in a dose dependent way [2]. In mouse macrophages, CGP 57380 concentration-dependently inhibited TNFα production stimulated by Escherichia coli lipopolysaccharide (LPS) through posttranscriptional regulation. Also, CGP 57380 inhibited eIF4E phosphorylation. These results suggested that adenine/uridine-rich elements (ARE)-containing TNFα mRNA required eIF4E phosphorylation for initiation of translation [3]. In bone marrow-derived macrophages, CGP 57380 significantly inhibited the production of proinflammatory cytokines monocyte chemoattractant protein-1, TNF and IL-6 [4].

References:
[1].  Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol, 2001, 21(16): 5500-5511.
[2].  Ishida M, Ishida T, Nakashima H, et al. Mnk1 is required for angiotensin II-induced protein synthesis in vascular smooth muscle cells. Circ Res, 2003, 93(12): 1218-1224.
[3].  Andersson K, Sundler R. Posttranscriptional regulation of TNFalpha expression via eukaryotic initiation factor 4E (eIF4E) phosphorylation in mouse macrophages. Cytokine, 2006, 33(1): 52-57.
[4].  Rowlett RM, Chrestensen CA, Nyce M, et al. MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. Am J Physiol Gastrointest Liver Physiol, 2008, 294(2): G452-459.