Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology

Kahina Hammam, Magali Saez-Ayala, Etienne Rebuffet, Laurent Gros, Sophie Lopez, Berengere Hajem, Martine Humbert, Emilie Baudelet, Stephane Audebert, Stephane Betzi, Adrien Lugari, Sebastien Combes, Sebastien Letard, Nathalie Casteran, Colin Mansfield, Alain Moussy, Paulo De Sepulveda, Xavier Morelli () and Patrice Dubreuil ()
Additional contact information
Kahina Hammam: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Magali Saez-Ayala: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Etienne Rebuffet: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Laurent Gros: AB Science
Sophie Lopez: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Berengere Hajem: AB Science
Martine Humbert: AB Science
Emilie Baudelet: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Stephane Audebert: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Stephane Betzi: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Adrien Lugari: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Sebastien Combes: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Sebastien Letard: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Nathalie Casteran: AB Science
Colin Mansfield: AB Science
Alain Moussy: AB Science
Paulo De Sepulveda: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Xavier Morelli: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue
Patrice Dubreuil: INSERM, CNRS, Aix-Marseille Univ, Institut Paoli-Calmettes, Equipe Labellisée Ligue

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01582-5

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DOI: 10.1038/s41467-017-01582-5

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