Mitogen-activated protein kinase interacting kinases (MNK) 1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. eFT508 Is a potent Inhibitor of MNK1 and MNK2 signaling and tumor growth. In all cell lines tested, eFT508 inhibited Ser209 phosphorylation of eIF4E with IC50 values ranging from 1.4 to 22 nM. This effect of eFT508 on eIF4E Ser209 phosphorylation is specific to MNK1/2 inhibition. Treatment of TMD8 cells for 48 h with eFT508 led to a dose-dependent reduction in secreted IL-6, IL-8, and TNFα. Taken together, eFT508 potently inhibited eIF4E phosphorylation, select mRNA stability, and pro-inflammatory cytokineproduction in DLBCL cells. eFT508 was well-tolerated at doses of 1 and 10 mg/kg QD as measured by lack of body weight loss, which corresponds to aminimal therapeutic index of≥10 in a TMD8 xenograft model. Furthermore, eFT508 treatment produced significant tumor growth inhibition (TGI) over a 10-fold dose range, achieving an average TGI of 71% and 75% when dosed orally at 1 and 10 mg/kg QD, respectively[2].
作用机制
eFT508 makes H-bond interactions with both hinge residues, Lys161 and Met162. The pyridone methyl interacts with the face of Phe159, and the Cys225 sulfur makes a Dunitz interaction[2].
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