Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

J Med Chem. 2018 Apr 26;61(8):3516-3540. doi: 10.1021/acs.jmedchem.7b01795. Epub 2018 Mar 29.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Catalytic Domain
  • Cell Line, Tumor
  • Drug Design
  • Eukaryotic Initiation Factor-4E / chemistry
  • Eukaryotic Initiation Factor-4E / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Molecular Structure
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Serine / chemistry
  • Signal Transduction / drug effects
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Spiro Compounds / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyridones
  • Pyrimidines
  • Spiro Compounds
  • Serine
  • MKNK1 protein, human
  • MKNK2 protein, human
  • Protein-Serine-Threonine Kinases
  • tomivosertib