Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung XXXX .

@entity1 @entity5 @entity19 @entity5290 @entity3 @entity563 @entity4043 @entity694 @entity320
Activation of the translation initiation factor 4E ( @entity4043 ) promotes malignant transformation and @entity3 . Signaling through the AKT-mTOR pathway activates @entity4043 by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates @entity4043 and allows binding to @entity5290 . @entity4043 can then be phosphorylated at @entity563 209 by the MAPK-interacting kinases (Mnk), which also interact with @entity5290 . Although dispensable for normal development, Mnk function and @entity4043 phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive @entity5 therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured @entity5 cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses @entity4043 phosphorylation for at least 4 hours in @entity1 xenograft @entity5 tissue and @entity19 liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 @entity320 pulmonary @entity3 as well as growth of subcutaneous HCT116 @entity694 xenograft @entity5 , without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable @entity5 therapeutic approach.
