Abstract
Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Drug Discovery
-
Eukaryotic Initiation Factor-4E / antagonists & inhibitors
-
Humans
-
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
-
Models, Molecular
-
Phosphorylation
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Structure-Activity Relationship
Substances
-
EIF4E protein, human
-
Eukaryotic Initiation Factor-4E
-
Intracellular Signaling Peptides and Proteins
-
Protein Kinase Inhibitors
-
MKNK1 protein, human
-
MKNK2 protein, human
-
Protein Serine-Threonine Kinases