Discovery\nof PARP1-Sparing Inhibitors for Protein\nADP-Ribosylation

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular\nADP-ribosylation\nplay important roles in human health. PARP inhibitors have found success\nin the clinic for cancer treatment. However, isoform-specific inhibitors\nare needed for improved safety. Here, we report the unexpected discovery\nof nicotinamide mimics that block non-PARP1-catalyzed ADP-ribosylation\nat micromolar concentrations. These PARP1-sparing PARP inhibitors\nrepresent first-in-class probes for ADP-ribosylation, shedding light\non the selective inhibition of PARPs.