Small-Molecule Inhibitors of PARPs: From Tools for Investigating ADP-Ribosylation to Therapeutics

Abstract

Over the last 60 years, poly-ADP-ribose polymerases (PARPs, 17 family members in humans) have emerged as important regulators of physiology and disease. Small-molecule inhibitors have been essential tools for unraveling PARP function, and recently the first PARP inhibitors have been approved for the treatment of various human cancers. However, inhibitors have only been developed for a few PARPs and in vitro profiling has revealed that many of these exhibit polypharmacology across the PARP family. In this review, we discuss the history, development, and current state of the field, highlighting the limitations and opportunities for PARP inhibitor development.

Fig. 1

PARPs catalyze the transfer of ADPr from NAD⁺ to target proteins. The majority of PARPs transfer either a single unit of ADPr, a process known as MARylation, whereas only four PARP family members transfer multiple units of ADPr, a process known as PARylation

Fig. 2

Structural features of the NAD⁺ binding site. a The bacterial toxin ExoA (PDB 2ZIT) bound to endogenous NAD⁺ shows how the H-Y-E catalytic triad, A-loop, and D-loop hold NAD⁺ in the binding site of a protein that catalyzes MARylation; b PARP1 in complex with a non-hydrolyzable NAD⁺ analog (PDB 6BHV) closely mirrors the structural interactions of endogenous NAD⁺ with ExoA; c Based on these crystal structures a simplified model of key interactions between NAD⁺ and the PARP catalytic domain reveals two important regions: the nicotinamide subsite (green) and the adenosine subsite (orange)

Fig. 3

Timeline of PARP inhibitor development

Fig. 4

Structures of common PARP inhibitors and their classifications

Fig. 5

Different small molecules access different regions of the NAD⁺ binding pocket. a PARP1 in complex with niraparib (PDB 4R6E); b PARP1 in complex with rucaparib (PDB 4RV6); b PARP2 in complex with olaparib (PDB 4TVJ); d PARP5b in complex with EB-47 (PDB 4TK5); e PARP5b in complex with IWR-1-endo (PDB 3UA9); f PARP5b in complex with G007-LK; g PARP10 in complex with 3-aminobenzamide (PDB 3HKV); h PARP14 in complex with 3-aminobenzamide (PDB 3GOY); i PARP14 in complex with compound 4s (PDB 5NQE)

Fig. 6

Major structural interactions of known PARP inhibitors with the NAD⁺ binding pocket. Crystal structures of known PARP inhibitors demonstrate how various small molecules can exploit different features in the nicotinamide and adenosine subsites in the NAD⁺ binding pocket

Fig. 7

Various NAD⁺ analogs and probes have been developed to monitor PARP activity. Salient modifications to NAD⁺ are highlighted in green

Fig. 8

Heat map showing the known IC₅₀ values of PARP inhibitors shown in Fig. 3. The IC₅₀ values used to generate this heat map derived from serval sources, as referenced in the text. In gray: values unknown