%0 Journal Article %A James, Dominic I. %A Smith, Kate M. %A Jordan, Allan M. %A Fairweather, Emma E. %A Griffiths, Louise A. %A Hamilton, Nicola S. %A Hitchin, James R. %A Hutton, Colin P. %A Jones, Stuart %A Kelly, Paul %A McGonagle, Alison E. %A Small, Helen %A Stowell, Alexandra I. J. %A Tucker, Julie %A Waddell, Ian D. %A Waszkowycz, Bohdan %A Ogilvie, Donald J. %D 2016 %T First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib %U https://acs.figshare.com/articles/journal_contribution/First-in-Class_Chemical_Probes_against_Poly_ADP-ribose_Glycohydrolase_PARG_Inhibit_DNA_Repair_with_Differential_Pharmacology_to_Olaparib/4012218 %R 10.1021/acschembio.6b00609.s001 %2 https://acs.figshare.com/ndownloader/files/6455913 %K chain persistence %K on-target pharmacology %K cell-active chemical probes %K Differential Pharmacology %K PARP inhibitor olaparib %K tool compounds %K cell-active tool compounds %K PARG inhibition %K Inhibit DNA Repair %K DDR %K DNA repair %K PARG inhibitor %K poly %K First-in-Class Chemical Probes %K strand breaks %K DNA damage response %K SSB %X 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). %I ACS Publications