First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib.
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).
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Dominic I
DI
James
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Kate M
KM
Smith
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Allan M
AM
Jordan
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Emma E
EE
Fairweather
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Louise A
LA
Griffiths
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Nicola S
NS
Hamilton
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
James R
JR
Hitchin
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Colin P
CP
Hutton
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Stuart
S
Jones
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Paul
P
Kelly
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Alison E
AE
McGonagle
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Helen
H
Small
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Alexandra I J
AI
Stowell
Structure and Biophysics, Discovery Sciences, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Julie
J
Tucker
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Ian D
ID
Waddell
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Bohdan
B
Waszkowycz
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, United Kingdom.
Donald J
DJ
Ogilvie
D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D015335:Molecular Probes / Q000737:chemistry*; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
D004791:Enzyme Inhibitors; D015335:Molecular Probes; D010793:Phthalazines; D010879:Piperazines; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; C531550:olaparib