Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases

Abstract

The recent clinical availability of the PARP inhibitor olaparib (Lynparza) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, we have selected indications, where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, to provide first-line options for therapeutic repurposing. These indications are as follows: acute ischaemic stroke; traumatic brain injury; septic shock; acute pancreatitis; and severe asthma and severe acute lung injury. In addition, chronic, devastating diseases, where alternative therapeutic options cannot halt disease development (e.g. Parkinson's disease, progressive multiple sclerosis or severe fibrotic diseases), should also be considered. We present a preclinical and clinical action plan for the repurposing of PARP inhibitors.

Linked articles: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Figure 1

Overview of key biological functions of PARP1. The top section shows the various domains of PARP, including its DNA‐binding domain, with its zinc fingers (ZnI, ZnII, ZnIII) that are essential for recognition of DNA strand breaks. This domain also contains the nuclear localization signal (NLS). The auto‐modification domain contains the conserved BRCT fold that serves an important protein : protein interaction module in DNA repair and cell signalling. This domain accepts PARP in the context of auto‐PARylation of PARP1. The catalytic domain contains the active site of the enzyme, where binding and cleavage of NAD+ takes place. It also contains the WGR domain, which is one of the domains involved in the RNA‐dependent activation of PARP1. Below the domains, on the right side, the structure of NAD⁺ is presented, with the nicotinamide part highlighted. The middle part of the figure shows the sequences of the PARylation process catalysed by PARP, starting with recognition of the DNA strand breaks by the DNA‐binding domain (grey ovals depicting the zinc fingers binding to the DNA breaks), followed by the catalytic activation of the enzyme and the cleavage of NAD⁺ the production of nicotinamide and the generation of PARP, which, in turn, PARylates various acceptor proteins as well as PARP itself. The consumption of NAD⁺ has metabolic and bioenergetic effects. PARP inhibitors prevent the binding of NAD⁺ to the active site of PARP and inhibit the catalytic activity of the enzyme. On the left side, the effect of PAR glycohydrolases and ARH3 is shown; these enzymes break down the PARP, leading to the liberation of free PAR.

Figure 2

Top section: Mechanisms responsible for the cytoprotective and anti‐inflammatory effects of PARP inhibitors on non‐oncological diseases. From left to right: First subpanel shows PARP activation and consequent NAD⁺ depletion. These processes can lead to cellular energetic deficit and cell dysfunction; inhibition of PARP prevents these processes and exerts cytoprotective effects (inhibition of cell necrosis). Second subpanel shows the role of PARP activation and free PAR polymers in inducing mitochondrial release of apoptosis‐inducing factor (AIF), which in turn induces cell death (parthanatos). Inhibition of PARP suppresses these processes and inhibits parthanatos. Third subpanel shows the role of PARP in liberating free PAR polymers, which on their own exert cytotoxic effects; inhibition of PARP prevents free PAR polymer formation and suppresses cell death. Fourth subpanel shows that PARylation contributes to activation of the proteasome through an interaction with RNF146; PARP inhibitors suppress these processes. Fifth subpanel shows the role of PARP in contributing to pro‐inflammatory signal transduction via enhancing JNK‐mediated (left sequence) and NF‐κB‐mediated (right sequence) activation of multiple genes and gene products. By inhibiting PARP, these processes are attenuated and inflammatory signalling can be attenuated. The five scenarios shown here can either be cell‐type and stimulus‐ and contex‐ dependent or can also occur simultaneously, depending on the pathophysiological condition. Taken together, PARP inhibitors, by blocking these processes, protect against cell death and suppress inflammatory responses. Bottom section: Mechanisms responsible for the cytotoxic effects of PARP inhibitors on oncological diseases. From left to right: The left side of the first subpanel shows that PARP contributes to single strand break repair, either through facilitating nucleotide excision repair (NER) via interactions with the WD40‐repeat protein DDB2 and the chromatin remodelling enzyme ALC1. The right side of the first subpanel shows that PARP contributes to BER through interaction with a variety of proteins including polynucleotide kinase 3′‐phosphatase (PNKP), X‐ray repair cross‐complementing 1 (XRCC1), aprataxin (APTX), Lig3 (DNA ligase 3) and APLF (a human protein putatively involved in DNA damage response). The second subpanel shows the role of PARP in DNA strand repair; the left side of this subpanel depicts the interactions of PARP with Lig IV (DNA ligase IV) and XRCC4 in the context of NHEJ (nonhomologous end joining); the right side of this subpanel depicts the interactions of PARP with components of the homologous repair (HR). In this context, PAR is recognized by several repair machineries, such as the BRCA1–BARD1 complex, the MRN complex and the hSSB1–INTS complex. The third subpanel depicts the role of PARP in the context of transcriptional regulation of WNT signalling, a pathway implicated in the process of androgen receptor expression. The fourth subpanel depicts the role of PARP in the maintenance of telomere length and chromatin stability, and the fifth subpanel shows the role of PARP in mitotic spindle formation. By inhibiting these processes, PARP inhibitors exert antiproliferative effects and cytotoxic effects, which can be exploited, with beneficial effects, in the therapy of various forms of cancers.

Figure 3

Pathogenetic role of PARP1 in various non‐oncological diseases. See Tables 3 and 4 for additional details.