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.

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