The poly(ADP-ribose) (PAR) post-translational modification is essential for diverse cellular functions, including regulation of transcription, response to DNA damage, and mitosis. Cellular PAR is predominantly synthesized by the enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a critical node in the DNA damage response pathway, and multiple potent PARP-1 inhibitors have been described, some of which show considerable promise in the clinic for the treatment of certain cancers. Cellular PAR is efficiently degraded by poly(ADP-ribose) glycohydrolase (PARG), an enzyme for which no potent, readily accessible, and specific inhibitors exist. Herein we report the discovery of small molecules that effectively inhibit PARG in vitro and in cellular lysates. These potent PARG inhibitors can be produced in two chemical steps from commercial starting materials and have complete specificity for PARG over the other known PAR glycohydrolase (ADP-ribosylhydrolase 3, ARH3) and over PARP-1, and thus will be useful tools to study the biochemistry of PAR signaling.

Color me yellow: Poly(ADP‐ribose) polymerases (PARPs) play a major role in cellular survival and maintenance of energy stores after genotoxic insult. The colorimetric PARP substrate ADP‐ribose‐pNP can be used to monitor PARP activity. By monitoring the production of p‐nitrophenolate, the kinetic parameters of PARP‐1, tankyrase, and PARP‐4 could be evaluated. ADP=adenosine diphosphate, pNP=p‐nitrophenoxy.

Gelb strahlt: Poly(ADP‐Ribose)‐Polymerasen (PARPs) spielen eine zentrale Rolle für das Überleben der Zellen und die Aufrechterhaltung von Energiespeichern nach einem gentoxischen Angriff. Das kolorimetrische PARP‐Substrat ADP‐Ribose‐pNP kann zur Verfolgung der PARP‐Aktivität genutzt werden. Anhand der Produktion von p‐Nitrophenolat sind die Kinetikparameter von PARP‐1, Tankyrase und PARP‐4 ermittelbar. ADP = Adenosindiphosphat, pNP = p‐Nitrophenoxy.

Compounds that contain phosphate and diphosphate moieties are not ideal biologic probes. Not only does their ionic character inhibit cell membrane permeability, but also, once inside a cell, the ester and the anhydride functionalities are likely targets for enzymatic cleavage. Thus, replacements for the phosphate motif are important as enzyme inhibitors, DNA or RNA analogs, phospholipid mimics, and phosphorylated metabolite analogs. To date, several classes of phosphate mimics have been developed that have been grouped into four categories: phosphorus‐containing, sulfur‐containing, dicarboxylates, and the novel cyclic mimics, which will be the focus of this review.

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