9HRC

Structure of MNK2 in complex with inhibitor NUCC-0201049

This is a non-PDB format compatible entry.

Summary for 9HRC

• Entry DOI: 10.2210/pdb9hrc/pdb
• Descriptor: MAP kinase-interacting serine/threonine-protein kinase 2, ZINC ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: mnk2, inhibitor, nucc-020149, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36077.72

Authors

Schiltz, G.E.,Vagadia, P.V. (deposition date: 2024-12-17, release date: 2025-03-12, Last modification date: 2025-03-26)

Primary citation

Vagadia, P.P.,Izquierdo-Ferrer, J.,Mazewski, C.,Blyth, G.,Beauchamp, E.M.,Clutter, M.R.,Stern, C.L.,Mishra, R.K.,Nahotko, D.,Small, S.,Eckerdt, F.,Platanias, L.C.,Schiltz, G.E.
Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia.
J.Med.Chem., 68:5824-5844, 2025

PubMed 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.

PubMed: 40033556
DOI: 10.1021/acs.jmedchem.4c03158

Experimental method

X-RAY DIFFRACTION (3.161 Å)