Abstract
MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5824-5844 |
| Number of pages | 21 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 68 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 13 2025 |
Funding
Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under Award Number NS113425 and the National Cancer Institute under award number CA121192. Some of the work was supported by P30CA060553. This work was supported by the Northwestern University High-Throughput Analysis Core, which received funding from the Lurie Cancer Center (NCI grant CA060553) and the Acoustic Liquid Handler SIG (NIH S10OD023681). This work made use of the IMSERC NMR facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois, the International Institute for Nanotechnology (IIN), and Northwestern University. This work made use of the IMSERC (RRID:SCR_017874) Crystallography facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), and Northwestern University. The authors thank Dr. Michael Cameron at the UF Scripps Institute for Biomedical Innovation and Technology for carrying out pharmacokinetics (PK) studies. PK data were collected using a mass spectrometer funded by NIH grant number 1S10OD030332-01. The authors thank Saman Shafaie for assistance with HRMS experiments. The authors thank Zhiquan Lei and Yongbo Zhang for their help with 2D NMR experiments. The authors acknowledge Crelux GmbH (Martinsried, Germany) for protein production and X-ray crystallography services.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
