2. Academic Validation
  3. Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

  • Eur J Med Chem. 2020 Aug 1;199:112355. doi: 10.1016/j.ejmech.2020.112355.
Nada Ibrahim 1,  Pascal Bonnet 2,  Jean-Daniel Brion 1,  Jean-François Peyrat 1,  Jerome Bignon 3,  Helene Levaique 3,  Béatrice Josselin 4,  Thomas Robert 4,  Pierre Colas 5,  Stéphane Bach 4,  Samir Messaoudi 1,  Mouad Alami 6,  Abdallah Hamze 7
Affiliations

Affiliations

  • 1 BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France.
  • 2 Institut de Chimie Organique et Analytique (ICOA), UMR7311 Université d'Orléans-CNRS, Rue de Chartres, BP 6759, 45067, Orléans, Cedex 2, France.
  • 3 Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France.
  • 4 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 5 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 6 BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France. Electronic address: mouad.alami@u-psud.fr.
  • 7 BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France. Electronic address: abdallah.hamze@u-psud.fr.
PMID: 32402934 DOI: 10.1016/j.ejmech.2020.112355
Abstract

In this work, unique flavopiridol analogs bearing thiosugars, Amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven Cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3β protein kinases.

Keywords

CDK10; CDK9; Cytotoxicity; Kinase inhibitors; Kinases; Structure-activity relationship.

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