PDD00017273

PD00017273 is an inhibitor of human PARG enzyme with IC50 of 26 nM and good selectivity over the two closest functional homologues, PARP1 and ARH3 (>100 μM). It is suitable for use in cellular assays (cell permeability data not available) and is not cytotoxic in HeLa cells up to 30 μM; however, different sensitivities in different cell lines are possible. Interestingly, the negative control (compound 6) also shows some weak activity in the Promega Glo assay. Off-target activity is not completely ruled out, since the compound was tested on a relatively small panel of 33 receptors and enzymes at 10 μM. PD00017273 is far a better compound compared with the previously reported PARG inhibitor, and it can used as chemical tool to investigate PARG biology. Due to high intrinsic clearance in HLM, the compound is not suitable for use for any in vivo studies.

PDD00017273 is a potent inhibitor of PARG in cells (EC₅₀=37 nM in a cellular PAR chain persistence assay) with little toxicity observed at 10 µM. While some degree of selectivity screening has been performed—for example, PDD00017273 is inactive at the related protein ARH3 and also at PARP1—a larger body of characterization data would be preferred for the informed deconvolution of cellular usage of the compound. The availability of a negative control compound inactive at the primary target increases the utlity of the compound. PDD00017273 shows poor metabolic stability in human liver microsomes and is thus unlikely to be useful as an in vivo probe.