Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Dysregulation of translation initiation factor 4E (eIF4E) is implicated in various cancers.
• Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) are crucial for eIF4E activation.

Purpose of the Study:

• To discover and develop novel dual inhibitors of MNK1 and MNK2.
• To evaluate the efficacy and pharmacokinetic profiles of these novel inhibitors.

Main Methods:

• Structure-activity relationship (SAR) studies were employed to optimize a fragment hit.
• Development of a novel pyridine-benzamide scaffold for dual MNK1/MNK2 inhibition.
• In vitro and in vivo pharmacokinetic assessments were performed.

Main Results:

• Discovery of potent dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold.
• Compounds demonstrated promising in vitro and in vivo pharmacokinetic profiles.
• Effective and potent on-target inhibition of eIF4E phosphorylation in cellular models was observed.

Conclusions:

• Novel pyridine-benzamide derivatives effectively inhibit MNK1/2 kinases and downstream eIF4E phosphorylation.
• These compounds represent a promising therapeutic strategy for cancers with eIF4E pathway dysregulation.
• The developed inhibitors exhibit favorable drug-like properties for further clinical development.