title: The Discovery of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine SIRT2 Inhibitors.
abstract: Isoform selective inhibitors of the sirtuins (NAD+-dependent histone deacetylases) should enable an in depth study of the molecular biology underpinning these targets and how they are deregulated in diseases such as cancer and neurodegeneration. Herein, we present the discovery of structurally novel SIRT2 inhibitors. Hit molecule8was discovered through the chemical synthesis and biological characterization of a small-molecule compound library based around the 10,11-dihydro-5H-dibenz[b,f]azepine scaffold.In vitroscreening assays revealed compound8to have an IC50of 18 μM against SIRT2 and to exhibit more than 30-fold selectivity compared to SIRT1. Cellular assays, performed on MCF-7 cells, confirmed thein vitroselectivity and showed hit8to have antiproliferative activity at a concentration of 30 μM. Computational studies were performed to predict the SIRT2 binding mode and to rationalise the observed selectivity.
authors: Department of Chemistry, Imperial College London, London, United Kingdom.
authors: Paolo
authors: P
authors: Di Fruscia
authors: Ka-Kei
authors: KK
authors: Ho
authors: Sasiwan
authors: S
authors: Laohasinnarong
authors: Mattaka
authors: M
authors: Khongkow
authors: Sebastian H B
authors: SH
authors: Kroll
authors: Suhail A
authors: SA
authors: Islam
authors: Michael J E
authors: MJ
authors: Sternberg
authors: Karin
authors: K
authors: Schmidtkunz
authors: Manfred
authors: M
authors: Jung
authors: Eric W-F
authors: EW
authors: Lam
authors: Matthew J
authors: MJ
authors: Fuchter