2. Academic Validation
  3. Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors

Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors

  • Bioorg Med Chem Lett. 2018 Apr 1;28(6):1001-1004. doi: 10.1016/j.bmcl.2018.02.034.
Andrea Milelli 1,  Chiara Marchetti 2,  Eleonora Turrini 3,  Elena Catanzaro 3,  Roberta Mazzone 4,  Daniela Tomaselli 4,  Carmela Fimognari 3,  Vincenzo Tumiatti 3,  Anna Minarini 2
Affiliations

Affiliations

  • 1 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • 3 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 4 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Roma, Italy.
PMID: 29496367 DOI: 10.1016/j.bmcl.2018.02.034
Abstract

Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for Anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine. Compound 4 emerged as the most promising of the synthesized series, showing good inhibitory activity towards HDAC1 and LSD1 either in vitro and in cell-based assay (Ki = 42.52 ± 8.94 nM and IC50 = 3.85 μM, respectively). Furthermore, at 70.0 µM compound 4 induced a more pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of dead cells) in MCF7 Cancer cell line.

Keywords

Dual-binding agents; Epigenetics; Histone deacetylase inhibitors; Lysine demethylase inhibitors; Polyamines.

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