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.

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.

• Authors: 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
• Journal: ChemMedChem (ChemMedChem) Vol. 10 Issue 1 Pg. 69-82 (Jan 2015) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25395356 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Histone Deacetylase Inhibitors
• ICL-SIRT078
• Neuroprotective Agents
• Pyrimidinones
• Thiophenes
• thieno(2,3-d)pyrimidin-4-one
• Sirtuin 2

Topics

• Animals
• Binding Sites
• Cell Line
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism)
• Drug Evaluation, Preclinical
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Histone Deacetylase Inhibitors (chemistry, pharmacology, therapeutic use)
• Humans
• MCF-7 Cells
• Molecular Docking Simulation
• Neuroprotective Agents (chemistry, pharmacology, therapeutic use)
• Parkinson Disease (drug therapy, metabolism, pathology)
• Protein Binding
• Protein Structure, Tertiary
• Pyrimidinones (chemistry, pharmacology, therapeutic use)
• Rats
• Sirtuin 2 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Thiophenes (chemistry, pharmacology, therapeutic use)