Fiche publication
Date publication
juillet 2017
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
Krieger V, Hamacher A, Gertzen CGW, Senger J, Zwinderman MRH, Marek M, Romier C, Dekker FJ, Kurz T, Jung M, Gohlke H, Kassack MU, Hansen FK
Lien Pubmed
Résumé
In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and a MTT assay for cytotoxicity. Based on their noteworthy activity in the cellular HDAC assay, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost sevenfold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.
Mots clés
Antineoplastic Agents, chemical synthesis, Cell Line, Tumor, Cell Proliferation, drug effects, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Histone Deacetylase Inhibitors, chemical synthesis, Histone Deacetylases, metabolism, Humans, Models, Molecular, Molecular Structure, Peptoids, chemical synthesis, Small Molecule Libraries, chemical synthesis, Structure-Activity Relationship
Référence
J. Med. Chem.. 2017 Jul 13;60(13):5493-5506
