The Discovery of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine SIRT2 Inhibitors

MedChemComm
Paolo Di FrusciaMatthew J Fuchter

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 molecule 8 was 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 vitro screening assays revealed compound 8 to have an IC50 of 18 μM against SIRT2 and to exhibit more than 30-fold selectivity compared to SIRT1. Cellular assays, performed on MCF-7 cells, confirmed the in vitro selectivity and showed hit 8 to 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.

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Citations

Jan 23, 2016·Organic & Biomolecular Chemistry·Ying-Ling Chiang, Hening Lin
Nov 11, 2014·Journal of Medicinal Chemistry·Tina SeifertKristina Luthman
Jun 11, 2015·Molecular BioSystems·Marco Daniele ParentiAlberto Del Rio
Jan 31, 2017·Journal of Medicinal Chemistry·Sandeep SundriyalMatthew J Fuchter
Mar 17, 2017·Journal of Chemical Information and Modeling·Shenzhen HuangShengyong Yang
Apr 13, 2018·Future Medicinal Chemistry·Ziyan ZhouXiaoming Zha
Dec 22, 2019·Scientific Reports·Shuntaro ChibaMasakazu Sekijima
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Oct 21, 2018·European Journal of Medicinal Chemistry·Yijie WangLiang Ouyang
Aug 20, 2021·Future Medicinal Chemistry·Tejashri Chavan, Aaron Muth

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