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

Paolo Di Fruscia, Emmanouil Zacharioudakis, Chang Liu, Sébastien Moniot, Sasiwan Laohasinnarong, Mattaka Khongkow, Ian F. Harrison, Konstantina Koltsida, Christopher R. Reynolds, Karin Schmidtkunz, Manfred Jung, Kathryn L. Chapman, Clemens Steegborn, David T. Dexter, Michael J.E. Sternberg, Eric W.F. Lam, Matthew J. Fuchter

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 iso-form-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±0.15mM 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.

Original languageEnglish (US)
Pages (from-to)69-82
Number of pages14
JournalChemMedChem
Volume10
Issue number1
DOIs
StatePublished - Jan 2015
Externally publishedYes

Keywords

  • Acetylation
  • Histone deacetylases (HDACs)
  • Parkinson's disease
  • SIRT
  • Sirtuins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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