2. Academic Validation
  3. Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

  • J Med Chem. 2022 Apr 28;65(8):6070-6087. doi: 10.1021/acs.jmedchem.1c01941.
Elisabeth Bou-Petit 1,  Stefan Hümmer 2 3,  Helena Alarcon 1,  Konstantin Slobodnyuk 2 3,  Marta Cano-Galietero 2 3,  Pedro Fuentes 2 3,  Pedro J Guijarro 2,  María José Muñoz 2 3,  Leticia Suarez-Cabrera 4,  Anna Santamaria 4,  Roger Estrada-Tejedor 1,  José I Borrell 1,  Santiago Ramón Y Cajal 2 3
Affiliations

Affiliations

  • 1 Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta, 390, 08017 Barcelona, Spain.
  • 2 Translational Molecular Pathology, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
  • 3 Spanish Biomedical Research Network Centre in Oncology (CIBERONC), 28029 Madrid, Spain.
  • 4 Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
PMID: 35417652 DOI: 10.1021/acs.jmedchem.1c01941
Abstract

Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

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