Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia
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.
Authors
- Matthew R. Clutter
- Frank Eckerdt (ORCID: https://orcid.org/0000-0001-6853-850X)
- Candice Mazewski (ORCID: https://orcid.org/0000-0001-7030-0998)
- Rama K. Mishra (ORCID: https://orcid.org/0000-0003-3608-2602)
- Sara Small (ORCID: https://orcid.org/0000-0003-1246-0250)
- Charlotte L. Stern (ORCID: https://orcid.org/0000-0002-9491-289X)
- Elspeth M. Beauchamp (ORCID: https://orcid.org/0009-0007-3180-2742)
- Gary E. Schiltz (ORCID: https://orcid.org/0000-0003-4180-5051)
- Dominik A. Nahotko (ORCID: https://orcid.org/0000-0001-5349-1139)
- Gavin T. Blyth
- Javier Izquierdo (ORCID: https://orcid.org/0000-0002-1086-1096)
- Purav P. Vagadia
- Leonidas C Platanias
Institutions
- Jesse Brown VA Medical Center (US)
- High Throughput Biology (United States) (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03158
- Citations
- 2
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.25
Funders
- National Science Foundation
- Northwestern University
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- International Institute for Nanotechnology, Northwestern University
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Division of Electrical, Communications and Cyber Systems