title: Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.
abstract: Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiedel
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.affiliation: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Berin
authors.initials: B
authors.lastname: Karaman
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Lehotzky
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Oláh
authors.affiliation: Institute of Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg , Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
authors.affiliation: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Institute of Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg , Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Einsle
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D000586:Amination; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D013844:Thiazoles; D014404:Tubulin; C474199:SIRT2 protein, human; D056565:Sirtuin 2