Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Dysregulated messenger RNA (mRNA) translation is a critical driver of tumorigenesis.
• Mitogen-activated protein kinase (MNK)1/2 kinases regulate mRNA translation by phosphorylating key proteins like eIF4E, integrating oncogenic and immune signals.
• Targeting mRNA translation offers a potential therapeutic strategy for cancer by controlling tumor and stromal cell signaling.

Purpose of the Study:

• To develop and evaluate Compound 23 (eFT508), a selective dual MNK1/2 inhibitor, for its ability to control oncogene signaling at the mRNA translation level.
• To assess the therapeutic potential of inhibiting MNK1/2 in cancer models.

Main Methods:

• Structure-guided design of Compound 23, a novel pyridone-aminal dual MNK1/2 inhibitor, utilizing stereoelectronic interactions.
• In vivo evaluation of Compound 23's antitumor activity in diffuse large B-cell lymphoma and solid tumor models.

Main Results:

• Compound 23 demonstrated potent in vivo antitumor activity in preclinical models.
• The compound's design represents a novel pyridone-aminal structure, described for the first time in kinase literature.
• Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation to enter clinical evaluation.

Conclusions:

• Inhibiting dysregulated mRNA translation via selective dual MNK1/2 inhibition is a promising therapeutic strategy for cancer.
• Compound 23 exhibits significant potential and is currently undergoing Phase 2 clinical trials for solid tumors and lymphoma.