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.
Department of Chemistry, Imperial College London, St. Kensington Campus, London SW7 2AZ, (UK).
Paolo
P
Di Fruscia
Emmanouil
E
Zacharioudakis
Chang
C
Liu
Sébastien
S
Moniot
Sasiwan
S
Laohasinnarong
Mattaka
M
Khongkow
Ian F
IF
Harrison
Konstantina
K
Koltsida
Christopher R
CR
Reynolds
Karin
K
Schmidtkunz
Manfred
M
Jung
Kathryn L
KL
Chapman
Clemens
C
Steegborn
David T
DT
Dexter
Michael J E
MJ
Sternberg
Eric W-F
EW
Lam
Matthew J
MJ
Fuchter
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; C000600807:ICL-SIRT078; D018696:Neuroprotective Agents; D011744:Pyrimidinones; D013876:Thiophenes; C542082:thieno(2,3-d)pyrimidin-4-one; D056565:Sirtuin 2
Parkinson’s disease; SIRT; acetylation; histone deacetylases (HDACs); sirtuins