2. Academic Validation
  3. Development of a Direct-to-Biology Platform to Discover Potent MNK Inhibitors

Development of a Direct-to-Biology Platform to Discover Potent MNK Inhibitors

  • J Med Chem. 2026 May 28;69(10):12543-12564. doi: 10.1021/acs.jmedchem.6c00368.
Purav P Vagadia 1,  Yingyu Mao 2,  Frank Eckerdt 3 4,  Joshua L Zhu 1,  Leonidas C Platanias 3 4 5,  Gary E Schiltz 1 4 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 2 High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.
  • 3 Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
  • 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, United States.
  • 5 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612, United States.
  • 6 Department of Pharmacology, Northwestern University, Chicago, Illinois 60611, United States.
PMID: 42126237 DOI: 10.1021/acs.jmedchem.6c00368
Abstract

Eukaryotic translation initiation factor 4E (eIF4E) plays an essential role in driving the translation of mRNAs that promote cell proliferation. Its activity is regulated through phosphorylation at Ser209 by MNK1/2 kinases, which are downstream effectors of mitogen-activated protein kinase signaling. Elevated eIF4E phosphorylation drives malignant progression in multiple cancers, including glioblastoma, where it promotes translation of key oncoproteins responsible for tumor growth and therapy resistance. Here, we report the development and application of a direct-to-biology (D2B) platform to rapidly optimize new MNK inhibitors for cellular inhibition. This approach combines plate-based library synthesis with an in-cell Western assay to efficiently generate structure-activity relationship (SAR) data and new compounds with potent cellular inhibition. Using this platform, we synthesized and tested >150 new analogs directly in cells, identifying inhibitors with IC50 values as low as 23 nM in LN229 cells. This work establishes a D2B approach as an effective strategy for efficient kinase inhibitor optimization.

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