Thienopyrimidinone based sirtuin-2 (SIRT2)-selective inhibitors bind in the ligand induced 'selectivity pocket'.

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Title: Thienopyrimidinone based sirtuin-2 (SIRT2)-selective inhibitors bind in the ligand induced 'selectivity pocket'.
Authors: Sundriyal, S
Moniot, S
Mahmud, Z
Yao, S
Di Fruscia, P
Reynolds, CR
Dexter, DT
Sternberg, MJ
Lam, EW
Steegborn, C
Fuchter, MJ
Item Type: Journal Article
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 co-crystal 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 understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
Issue Date: 30-Jan-2017
Date of Acceptance: 17-Nov-2016
ISSN: 0022-2623
Publisher: American Chemical Society
Start Page: 1928
End Page: 1945
Journal / Book Title: Journal of Medicinal Chemistry
Volume: 60
Issue: 5
Copyright Statement: © 2017 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License (, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: C21484/A6944/A9520/G20971
RDB01 79560
Keywords: Medicinal & Biomolecular Chemistry
0304 Medicinal And Biomolecular Chemistry
1115 Pharmacology And Pharmaceutical Sciences
0305 Organic Chemistry
Publication Status: Published
Conference Place: United States
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Natural Sciences

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