TY - JOUR
T1 - 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
AU - Di Fruscia, Paolo
AU - Zacharioudakis, Emmanouil
AU - Liu, Chang
AU - Moniot, Sébastien
AU - Laohasinnarong, Sasiwan
AU - Khongkow, Mattaka
AU - Harrison, Ian F.
AU - Koltsida, Konstantina
AU - Reynolds, Christopher R.
AU - Schmidtkunz, Karin
AU - Jung, Manfred
AU - Chapman, Kathryn L.
AU - Steegborn, Clemens
AU - Dexter, David T.
AU - Sternberg, Michael J.E.
AU - Lam, Eric W.F.
AU - Fuchter, Matthew J.
N1 - Publisher Copyright:
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
KW - Acetylation
KW - Histone deacetylases (HDACs)
KW - Parkinson's disease
KW - SIRT
KW - Sirtuins
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UR - http://www.scopus.com/inward/citedby.url?scp=84919778888&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201402431
DO - 10.1002/cmdc.201402431
M3 - Article
C2 - 25395356
AN - SCOPUS:84919778888
SN - 1860-7179
VL - 10
SP - 69
EP - 82
JO - ChemMedChem
JF - ChemMedChem
IS - 1
ER -