1. Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor
- Author
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Elisabeth Bou-Petit, Stefan Hümmer, Helena Alarcon, Konstantin Slobodnyuk, Marta Cano-Galietero, Pedro Fuentes, Pedro J. Guijarro, María José Muñoz, Leticia Suarez-Cabrera, Anna Santamaria, Roger Estrada-Tejedor, José I. Borrell, Santiago Ramón y Cajal, Institut Català de la Salut, [Bou-Petit E, Alarcon H] Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain. [Hümmer S, Slobodnyuk K, Cano-Galietero M, Muñoz MJ, Ramón Y Cajal S] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain. [Fuentes P] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain. Laboratory of Cancer Metabolism, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. [Guijarro PJ] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Suarez-Cabrera L, Santamaria A] Laboratori de Cicle Cel·lular i Càncer, Grup de Recerca Biomèdica en Urologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Models, Molecular ,Càncer - Tractament ,técnicas de investigación::modelos teóricos::modelos moleculares [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Intracellular Signaling Peptides and Proteins ,Medicaments antineoplàstics - Ús terapèutic ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,Protein Serine-Threonine Kinases ,Molècules - Models ,Neoplasms [DISEASES] ,neoplasias [ENFERMEDADES] ,Adenosine Triphosphate ,Investigative Techniques::Models, Theoretical::Models, Molecular [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Drug Discovery ,Molecular Medicine ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] ,Signal Transduction - Abstract
Inhibidor de MNK1; Oncología Inhibidor de MNK1; Oncologia MNK1 inhibitor; Oncology 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. This work was supported by the Instituto de Salud Carlos III (PI17/02247), (PI20/01687), and CIBERONC (CB16/12/00363). S.R.y.C. acknowledges support from the Generalitat de Catalunya (2017-9015-385045). E. Bou-Petit thanks the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017 FI_B2 00139) and the European Social Funds for her predoctoral fellowship.
- Published
- 2022