title: Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket.
abstract: Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
authors.affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sundriyal
authors.affiliation: Department of Biochemistry, University of Bayreuth , Universitaetsstrasse 30, 95447 Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Department of Surgery & Cancer, Imperial College London , Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
authors.forename: Zimam
authors.initials: Z
authors.lastname: Mahmud
authors.affiliation: Department of Surgery & Cancer, Imperial College London , Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
authors.forename: Shang
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Paolo
authors.initials: P
authors.lastname: Di Fruscia
authors.affiliation: Department of Life Sciences, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Reynolds
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Imperial College London , London W12 0NN, U.K.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
authors.affiliation: Department of Life Sciences, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
authors.affiliation: Department of Surgery & Cancer, Imperial College London , Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Biochemistry, University of Bayreuth , Universitaetsstrasse 30, 95447 Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Matthew J
authors.identifier: 0000-0002-1767-7072
authors.initials: MJ
authors.lastname: Fuchter
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D062105:Molecular Docking Simulation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D058924:Thienopyridines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008024:Ligands; D058924:Thienopyridines; D056565:Sirtuin 2