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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 DOI Help

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).

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography

Added On: 06/12/2016 15:30

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