Imperial College London
Alternate

ProfessorMichaelSternberg

Faculty of Natural Sciences, Department of Life Sciences

Director, Systems Biology and Bioinformatics Centre
 
 
 
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Contact

 

+44 (0)20 7594 5212m.sternberg Website

 
 
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Location

 

306Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sundriyal:2017:10.1021/acsjmedchem.6b01690,
author = {Sundriyal, S and Moniot, S and Mahmud, Z and Yao, S and Di, Fruscia P and Reynolds, CR and Dexter, DT and Sternberg, MJE and Lam, EW-F and Steegborn, C and Fuchter, MJ},
doi = {10.1021/acsjmedchem.6b01690},
journal = {JOURNAL OF MEDICINAL CHEMISTRY},
pages = {1928--1945},
title = {Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket},
url = {http://dx.doi.org/10.1021/acsjmedchem.6b01690},
volume = {60},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Sundriyal,S
AU  - Moniot,S
AU  - Mahmud,Z
AU  - Yao,S
AU  - Di,Fruscia P
AU  - Reynolds,CR
AU  - Dexter,DT
AU  - Sternberg,MJE
AU  - Lam,EW-F
AU  - Steegborn,C
AU  - Fuchter,MJ
DO  - 10.1021/acsjmedchem.6b01690
EP  - 1945
PY  - 2017///
SN  - 0022-2623
SP  - 1928
TI  - Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket
T2  - JOURNAL OF MEDICINAL CHEMISTRY
UR  - http://dx.doi.org/10.1021/acsjmedchem.6b01690
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000396296100021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/44816
VL  - 60
ER  -
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