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First-in-class chemical probes against poly(ADP-ribose) glycohydrolase (PARG) inhibit dna repair with differential pharmacology to olaparib
DOI:
10.1021/acschembio.6b00609
Authors:
Dominic I.
James
(Cancer Research UK Manchester Institute, University of Manchester)
,
Kate M.
Smith
(Cancer Research UK Manchester Institute, University of Manchester)
,
Allan M.
Jordan
(Cancer Research UK Manchester Institute, University of Manchester)
,
Emma E.
Fairweather
(Cancer Research UK Manchester Institute, University of Manchester)
,
Louise A.
Griffiths
(Cancer Research UK Manchester Institute, University of Manchester)
,
Nicola S.
Hamilton
(Cancer Research UK Manchester Institute, University of Manchester)
,
James R.
Hitchin
(Cancer Research UK Manchester Institute, University of Manchester)
,
Colin P.
Hutton
(Cancer Research UK Manchester Institute, University of Manchester)
,
Stuart
Jones
(Cancer Research UK Manchester Institute, University of Manchester)
,
Paul
Kelly
(Cancer Research UK Manchester Institute, University of Manchester)
,
Alison E.
Mcgonagle
(Cancer Research UK Manchester Institute, University of Manchester)
,
Helen
Small
(Cancer Research UK Manchester Institute, University of Manchester)
,
Alexandra I. J.
Stowell
(Cancer Research UK Manchester Institute, University of Manchester)
,
Julie
Tucker
(AstraZeneca)
,
Ian D.
Waddell
(Cancer Research UK Manchester Institute, University of Manchester)
,
Bohdan
Waszkowycz
(Cancer Research UK Manchester Institute, University of Manchester)
,
Donald J.
Ogilvie
(Cancer Research UK Manchester Institute, University of Manchester)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Acs Chemical Biology
, VOL 11
, PAGES 3179 - 3190
State:
Published (Approved)
Published:
November 2016
Abstract: The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity. Using one of these tool compounds, we demonstrate pharmacology consistent with PARG inhibition. Further, while the roles of PARG and poly(ADP-ribose) polymerase (PARP) are closely intertwined, we demonstrate that the pharmacology of a PARG inhibitor differs from that observed with the more thoroughly studied PARP inhibitor olaparib. We believe that these tools will facilitate a wider understanding of this important component of DNA repair and may enable the development of novel therapeutic agents exploiting the critical dependence of tumors on the DNA damage response (DDR).
Journal Keywords: Assays; Cells; Inhibitors; Inhibition
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I02-Macromolecular Crystallography
Added On:
06/12/2016 15:30
Documents:
acschembio.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)