生物活性

• 描述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].