Open AccessOvercoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
Author(s) -
Elisabeth BouPetit,
Stefan Hümmer,
Helena Alarcon,
Konstantin Slobodnyuk,
Marta Cano-Galietero,
Pedro Juan Barrios Fuentes,
Pedro J. Guijarro,
María José Muñoz,
Leticia SuárezCabrera,
Anna Santamaría,
Roger EstradaTejedor,
José I. Borrell,
Santiago Ramón y Cajal
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01941
Subject(s) - kinase , chemistry , mode of action , cancer research , microbiology and biotechnology , small molecule , rational design , computational biology , biochemistry , pharmacology , biology , genetics
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.