Pharmacological characterisation of novel, cell active, inhibitors of Poly(ADP-ribose glycohydrolase (PARG)

Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. Total PARG deficiency leads to cell death whilst PARG depletion, using RNAi, leads to pleiotropic effects such as PAR chain persistence, progression of single- to double-strand DNA lesions and NAD+ depletion.Whilst efforts to develop small molecule inhibitors of PARG activity have generally been hampered by poor physiochemical properties, off-target pharmacology and a lack of cell permeability, we have now developed a series of PARG inhibitors which have proved to be useful biological tool compounds. Displaying selective activity in both biochemical and, more importantly, cellular assays of PARG function, these derivatives have allowed an exploration of the phenotypes resulting from reversible, pharmacological PARG inhibition.