Dysregulated translation of mRNA plays a major role in tumorigenesis. 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. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

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The oxidative homocoupling of para-alkenyl phenols and subsequent trapping of the resulting quinone methide with a variety of oxygen and nitrogen nucleophiles were achieved. Both β-β and β-O coupling isomers can be synthesized via either C–C coupling and two nucleophilic additions of one water molecule (β-β isomer) or C–O coupling followed by one nucleophilic addition of a water molecule (β-O isomer), respectively. Selectivity between these outcomes was achieved by leveraging the understanding of the mechanism. Specifically, a qualitative predictive model for the selectivity of the coupling was formulated based on catalyst electronics, solvent polarity, and concentration.

Alkenyl phenols are utilized by nature in the construction of one of the most important biopolymers, lignin. Using similar building blocks, an array of distinct structures can be formed by...

Scheme5.Scopeo ft he cross-coupling of 3-oxindoles with simple arenes.Scheme3.Scope of the coupling of 3-oxindolesw ith indoles.[a] Reactionat 80 8C.