Rational design of selective inhibitors of PARP4

PARPs (PARP1-16 in humans) are a large family of ADP-ribosyltransferases (ARTs) that have diverse roles in cellular physiology and pathophysiology. Most PARP family members mediate mono-ADP-ribosylation (MARylation) of targets. The function of PARP-mediated MARylation in cells is poorly characterized, due in large part to the paucity of selective small molecule inhibitors of the catalytic activity of individual PARP enzymes. Herein we describe the rational design of selective small molecule inhibitors of PARP4 (also known as vPARP). These inhibitors are based on a quinazolin-4(3H)-one scaffold, and contain substituents at the C-8 position designed to exploit a unique threonine (Thr484, human PARP4 numbering) in the PARP4 nicotinamide sub-pocket. Our most potent analog, AEP07, which contains an iodine at the C-8 position, is at least 12-fold selective over other PARP family members. AEP07 will serve as a useful lead compound for the further development of PARP4 inhibitors that can be used to probe the cellular functions of PARP4 catalytic activity.