Journal ArticleDOI
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.
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 Lam,Matthew J. Fuchter +16 more
Reads0
Chats0
TLDR
In concordance with the recent reports that suggest SIRT2 inhibition is a potential strategy for the treatment of Parkinson’s disease, compound ICL‐SIRT078 has a significant neuroprotective effect in a lactacystin‐induced model of Parkinsonian neuronal cell death in the N27 cell line.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.read more
Citations
More filters
Journal ArticleDOI
Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)
Matthias Schiedel,Daniel Herp,Sören Hammelmann,Sören Swyter,Attila Lehotzky,Dina Robaa,Judit Oláh,Judit Ovádi,Wolfgang Sippl,Manfred Jung +9 more
TL;DR: This SirReal-based PROTAC is the first example of a probe that is able to chemically induce the degradation of an epigenetic eraser protein and can be readily adapted to alkynylated ligands of other targets.
Journal ArticleDOI
The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease
Rita Machado de Oliveira,Hugo Vicente Miranda,Laetitia Francelle,Raquel Pinho,Raquel Pinho,Éva M. Szegö,Renato Martinho,Francesca Munari,Francesca Munari,Diana F. Lázaro,Sébastien Moniot,Patrícia Guerreiro,Luis Fonseca-Ornelas,Zrinka Marijanovic,Pedro Antas,Ellen Gerhardt,Francisco J. Enguita,Bruno Fauvet,Deborah Penque,Teresa F. Pais,Qiang Tong,Stefan Becker,Sebastian Kügler,Hilal A. Lashuel,Clemens Steegborn,Markus Zweckstetter,Markus Zweckstetter,Markus Zweckstetter,Tiago F. Outeiro +28 more
TL;DR: It is found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2, demonstrating the potential therapeutic value of sIRTuin 2 inhibition in synucleinopathies.
Journal ArticleDOI
The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance.
TL;DR: A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as wellAs crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.
Journal ArticleDOI
An overview of Sirtuins as potential therapeutic target: Structure, function and modulators.
Yijie Wang,Jun He,Mengya Liao,Mingxing Hu,Wenzhen Li,Hongling Ouyang,Xin Wang,Tinghong Ye,Yiwen Zhang,Liang Ouyang +9 more
TL;DR: A comprehensive review of the structure, function and modulators of Sirtuins is presented, which is expected to be beneficial to relevant studies.
Journal ArticleDOI
SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation.
TL;DR: Data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF‐κB p65 acetylation and activation and up‐regulation of its target genes, including aquaporin 4 (AQP4), MMP‐9, and pro‐inflammatory cytokines.
References
More filters
Journal ArticleDOI
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling
TL;DR: The SWISS-MODEL workspace is a web-based integrated service dedicated to protein structure homology modelling that assists and guides the user in building protein homology models at different levels of complexity.
Journal ArticleDOI
Development and validation of a genetic algorithm for flexible docking.
TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.
Journal ArticleDOI
Drug-like properties and the causes of poor solubility and poor permeability
TL;DR: There are currently about 10000 drug-like compounds, and true diversity does not exist in experimental combinatorial chemistry screening libraries because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates.
Journal ArticleDOI
Histone deacetylases (HDACs): characterization of the classical HDAC family
Annemieke J.M. de Ruijter,Albert H. van Gennip,Huib N. Caron,Stephan Kemp,André B.P. van Kuilenburg +4 more
TL;DR: In this paper, a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity is presented.
Journal ArticleDOI
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
TL;DR: A number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens are described.
Related Papers (5)
Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.
SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis
Ruth Luthi-Carter,David Taylor,Judit Pallos,Emmanuel Lambert,Allison M. Amore,Alex Parker,Hilary Moffitt,Donna L. Smith,Heike Runne,Ozgun Gokce,Alexandre Kuhn,Zhongmin Xiang,Michele M. Maxwell,Steven A. Reeves,Gillian P. Bates,Christian Neri,Leslie M. Thompson,J. Lawrence Marsh,Aleksey G. Kazantsev +18 more