Avoid the trap: Targeting PARP1 beyond human malignancy

Abstract

PARP1 is a poly(ADP-ribose) polymerase (PARP) enzyme that plays a critical role in regulating DNA damage response. The main enzymatic function of PARP1 is to catalyze a protein post-translational modification known as poly(ADP-ribosyl)ation (PARylation). Human cancers with homologous recombination deficiency are highly sensitive to PARP1 inhibitors. PARP1 is aberrantly activated in many non-oncological diseases, leading to the excessive NAD⁺ depletion and PAR formation, thus causing cell death and tissue damage. PARP1 deletion offers a profound protective effect in the relevant animal models. However, many of the current PARP1 inhibitors also induce PARP1 trapping, which drives subsequent DNA damage, innate immune response and cytotoxicity. This minireview provides an overview of the basic biology of PARP1 trapping, and its implications in disease. Furthermore, we also discuss the recent development of PARP1 PROTAC compounds, and their utility as "non-trapping" PARP1 degraders for the potential amelioration of non-oncological diseases driven by aberrant PARP1 activation.

Keywords: BRCA; NAD(+); PARP; breast cancer; cell death; ischemia reperfusion injury; neurodegeneration; ovarian cancer; phase transition; poly(ADP-ribose); stroke.

Figure 1.

PROTAC compounds block the enzymatic activity of PARP1 without eliciting PARP1 trapping. (Left) A simplified model of PARP1 trapping, and its role in various diseases. PARP1 is hyper-activated in many non-oncological diseases. Although many of the current PARPi inhibit PARP1, they also trap PARP1, leading to DNA damage, innate immune response, and cytotoxicity. In contrast, PARP1 degraders block both the enzymatic and scaffolding effects of PARP1. (Right) The structure and mechanism of action of a recently described PARP1 PROTAC compound (i.e., iRucaparib-AP6).

Figure 2.

Comparison between a PARP1 inhibitor and a PROTAC-based PARP1 degrader.