2. Academic Validation
  3. Synthesis of a selective HDAC6 inhibitor active in neuroblasts

Synthesis of a selective HDAC6 inhibitor active in neuroblasts

  • Bioorg Med Chem Lett. 2016 Oct 15;26(20):4955-4959. doi: 10.1016/j.bmcl.2016.09.011.
Vincent Zwick 1,  Claudia A Simões-Pires 1,  Alessandra Nurisso 2,  Charlotte Petit 1,  Carolina Dos Santos Passos 1,  Giuseppe Marco Randazzo 1,  Nadine Martinet 3,  Philippe Bertrand 4,  Muriel Cuendet 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
  • 2 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland; Département de Biochimie, Université de Montréal, H3C 3J7 Montréal, Québec, Canada.
  • 3 Institut de chimie, UMR CNRS 7272, UNSA, F-06108 Nice, France.
  • 4 Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 521106, B28, 86073 Poitiers, France; Réseau Epigénétique du Cancéropôle Grand Ouest, France.
  • 5 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland. Electronic address: muriel.cuendet@unige.ch.
PMID: 27650925 DOI: 10.1016/j.bmcl.2016.09.011
Abstract

In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 Inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was designed and synthetized. This compound was predicted to have potential for BBB penetration based on in silico and in vitro evaluation of passive permeability. When tested for its HDAC inhibitory activity, the IC50 value of compound 3 towards HDAC6 was in the nM range in both enzymatic and cell-based assays. Compound 3 showed a cell-based selectivity profile close to that of tubastatin A in SH-SY5Y human neuroblastoma cells, and a good BBB permeability profile.

Keywords

HDAC6; Histone deacetylases; Isoform selectivity; Neuroblastoma cells; PAMPA.

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