2. Academic Validation
  3. Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia

Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia

  • J Med Chem. 2025 Mar 13;68(5):5824-5844. doi: 10.1021/acs.jmedchem.4c03158.
Purav P Vagadia 1,  Javier Izquierdo-Ferrer 1,  Candice Mazewski 2,  Gavin Blyth 2,  Elspeth M Beauchamp 2 3 4,  Matthew R Clutter 2 5,  Charlotte L Stern 1 6,  Rama K Mishra 1,  Dominik Nahotko 2,  Sara Small 2 3,  Frank Eckerdt 2 3,  Leonidas C Platanias 2 3 4,  Gary E Schiltz 1 2 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
  • 3 Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
  • 4 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612, United States.
  • 5 High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.
  • 6 The Integrated Molecular Structure Education and Research Center (IMSERC), Northwestern University, Evanston, Illinois 60208, United States.
  • 7 Department of Pharmacology, Northwestern University, Chicago, Illinois 60611, United States.
PMID: 40033556 DOI: 10.1021/acs.jmedchem.4c03158
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172457
    MNK1 Inhibitor
    MNK