title: Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach.
abstract: Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Cui
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Kamal
authors.forename: Teng
authors.initials: T
authors.lastname: Ai
authors.forename: Yanli
authors.initials: Y
authors.lastname: Xu
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D015394:Molecular Structure; D009536:Niacinamide / Q000737:chemistry; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry; D013498:Suramin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D013451:Sulfonic Acids; D009536:Niacinamide; D013498:Suramin; C474199:SIRT2 protein, human; D056565:Sirtuin 2