Affordable Access

deepdyve-link
Publisher Website

The discovery of a highly selective 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 inhibitor that is neuroprotective in an in vitro Parkinson's disease model.

Authors
  • Di Fruscia, Paolo
  • Zacharioudakis, Emmanouil
  • Liu, Chang
  • Moniot, Sébastien
  • Laohasinnarong, Sasiwan
  • Khongkow, Mattaka
  • Harrison, Ian F
  • Koltsida, Konstantina
  • Reynolds, Christopher R
  • Schmidtkunz, Karin
  • Jung, Manfred
  • Chapman, Kathryn L
  • Steegborn, Clemens
  • Dexter, David T
  • Sternberg, Michael J E
  • Lam, Eric W-F
  • Fuchter, Matthew J
Type
Published Article
Journal
ChemMedChem
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 01, 2015
Volume
10
Issue
1
Pages
69–82
Identifiers
DOI: 10.1002/cmdc.201402431
PMID: 25395356
Source
Medline
Keywords
License
Unknown

Abstract

Sirtuins, NAD(+) -dependent histone deacetylases (HDACs), have recently emerged as potential therapeutic targets for the treatment of a variety of diseases. The discovery of potent and isoform-selective inhibitors of this enzyme family should provide chemical tools to help determine the roles of these targets and validate their therapeutic value. Herein, we report the discovery of a novel class of highly selective SIRT2 inhibitors, identified by pharmacophore screening. We report the identification and validation of 3-((2-methoxynaphthalen-1-yl)methyl)-7-((pyridin-3-ylmethyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (ICL-SIRT078), a substrate-competitive SIRT2 inhibitor with a Ki value of 0.62 ± 0.15 μM and more than 50-fold selectivity against SIRT1, 3 and 5. Treatment of MCF-7 breast cancer cells with ICL-SIRT078 results in hyperacetylation of α-tubulin, an established SIRT2 biomarker, at doses comparable with the biochemical IC50 data, while suppressing MCF-7 proliferation at higher concentrations. In concordance with the recent reports that suggest SIRT2 inhibition is a potential strategy for the treatment of Parkinson's disease, we find that compound ICL-SIRT078 has a significant neuroprotective effect in a lactacystin-induced model of Parkinsonian neuronal cell death in the N27 cell line. These results encourage further investigation into the effects of ICL-SIRT078, or an optimised derivative thereof, as a candidate neuroprotective agent in in vivo models of Parkinson's disease.

Report this publication

Statistics

Seen <100 times