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Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

[Image: see text] 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...

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Autores principales: Bou-Petit, Elisabeth, Hümmer, Stefan, Alarcon, Helena, Slobodnyuk, Konstantin, Cano-Galietero, Marta, Fuentes, Pedro, Guijarro, Pedro J., Muñoz, María José, Suarez-Cabrera, Leticia, Santamaria, Anna, Estrada-Tejedor, Roger, Borrell, José I., Ramón y Cajal, Santiago
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059116/
https://www.ncbi.nlm.nih.gov/pubmed/35417652
http://dx.doi.org/10.1021/acs.jmedchem.1c01941
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author Bou-Petit, Elisabeth
Hümmer, Stefan
Alarcon, Helena
Slobodnyuk, Konstantin
Cano-Galietero, Marta
Fuentes, Pedro
Guijarro, Pedro J.
Muñoz, María José
Suarez-Cabrera, Leticia
Santamaria, Anna
Estrada-Tejedor, Roger
Borrell, José I.
Ramón y Cajal, Santiago
author_facet Bou-Petit, Elisabeth
Hümmer, Stefan
Alarcon, Helena
Slobodnyuk, Konstantin
Cano-Galietero, Marta
Fuentes, Pedro
Guijarro, Pedro J.
Muñoz, María José
Suarez-Cabrera, Leticia
Santamaria, Anna
Estrada-Tejedor, Roger
Borrell, José I.
Ramón y Cajal, Santiago
author_sort Bou-Petit, Elisabeth
collection PubMed
description [Image: see text] 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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spelling pubmed-90591162022-05-03 Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor Bou-Petit, Elisabeth Hümmer, Stefan Alarcon, Helena Slobodnyuk, Konstantin Cano-Galietero, Marta Fuentes, Pedro Guijarro, Pedro J. Muñoz, María José Suarez-Cabrera, Leticia Santamaria, Anna Estrada-Tejedor, Roger Borrell, José I. Ramón y Cajal, Santiago J Med Chem [Image: see text] 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. American Chemical Society 2022-04-13 2022-04-28 /pmc/articles/PMC9059116/ /pubmed/35417652 http://dx.doi.org/10.1021/acs.jmedchem.1c01941 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Bou-Petit, Elisabeth
Hümmer, Stefan
Alarcon, Helena
Slobodnyuk, Konstantin
Cano-Galietero, Marta
Fuentes, Pedro
Guijarro, Pedro J.
Muñoz, María José
Suarez-Cabrera, Leticia
Santamaria, Anna
Estrada-Tejedor, Roger
Borrell, José I.
Ramón y Cajal, Santiago
Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title_full Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title_fullStr Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title_full_unstemmed Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title_short Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
title_sort overcoming paradoxical kinase priming by a novel mnk1 inhibitor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059116/
https://www.ncbi.nlm.nih.gov/pubmed/35417652
http://dx.doi.org/10.1021/acs.jmedchem.1c01941
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