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

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. Hit discovery: Through ligand‐based virtual screening validation, ICL‐SIRT078, a cell‐active 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 was identified. In addition, ICL‐SIRT078 shows a significant neuroprotective effect in a lactacystin‐induced model of Parkinsonian neuronal cell death in the N27 cell line. ICL‐SIRT078, or an optimised derivative thereof, warrants further investigation as a neuroprotective agent in in vivo models of Parkinson's disease.