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

doi:10.1111/bph.13748

Review

. 2018 Jan;175(2):192-222.

doi: 10.1111/bph.13748. Epub 2017 Mar 26.

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

Nathan A Berger¹, Valerie C Besson², A Hamid Boulares³, Alexander Bürkle⁴, Alberto Chiarugi⁵, Robert S Clark⁶, Nicola J Curtin⁷, Salvatore Cuzzocrea⁸, Ted M Dawson⁹, Valina L Dawson¹⁰, György Haskó¹¹, Lucas Liaudet¹², Flavio Moroni¹³, Pál Pacher¹⁴, Peter Radermacher¹⁵, Andrew L Salzman¹⁶, Solomon H Snyder¹⁷, Francisco Garcia Soriano¹⁸, Robert P Strosznajder¹⁹, Balázs Sümegi²⁰, Raymond A Swanson²¹, Csaba Szabo²²

Affiliations

¹ Center for Science, Health and Society, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
² EA4475 - Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
³ The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
⁴ Molecular Toxicology Group, Department of Biology, University of Konstanz, Constance, Germany.
⁵ Department of Health Sciences, Section of Clinical Pharmacology and Oncology, Headache Center - University Hospital, University of Florence, Florence, Italy.
⁶ Department of Critical Care Medicine and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Newcastle University, Northern Institute for Cancer Research, Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK.
⁸ Department of Pharmacology, University of Messina, Messina, Italy.
⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering and Department of Neurology and Department of Pharmacology and Molecular Sciences and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering and Department of Neurology and Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Surgery and Center for Immunity and Inflammation, Rutgers-New Jersey Medical School, Newark, NJ, USA.
¹² Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland.
¹³ Department of Neuroscience, Università degli Studi di Firenze, Florence, Italy.
¹⁴ Laboratory of Physiologic Studies, Section on Oxidative Stress Tissue Injury, NIAAA, NIH, Bethesda, USA.
¹⁵ Institute of Anesthesiological Pathophysiology and Process Engineering, University Hospital, Ulm, Germany.
¹⁶ Radikal Therapeutics Inc., West Tisbury, MA, USA.
¹⁷ Department of Neurology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
¹⁹ Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
²⁰ Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
²¹ Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
²² Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.

PMID: 28213892
PMCID: PMC5758399
DOI: 10.1111/bph.13748

Review

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

Nathan A Berger et al. Br J Pharmacol. 2018 Jan.

. 2018 Jan;175(2):192-222.

doi: 10.1111/bph.13748. Epub 2017 Mar 26.

Authors

Affiliations

¹ Center for Science, Health and Society, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
² EA4475 - Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
³ The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
⁴ Molecular Toxicology Group, Department of Biology, University of Konstanz, Constance, Germany.
⁵ Department of Health Sciences, Section of Clinical Pharmacology and Oncology, Headache Center - University Hospital, University of Florence, Florence, Italy.
⁶ Department of Critical Care Medicine and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Newcastle University, Northern Institute for Cancer Research, Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK.
⁸ Department of Pharmacology, University of Messina, Messina, Italy.
⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering and Department of Neurology and Department of Pharmacology and Molecular Sciences and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering and Department of Neurology and Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Surgery and Center for Immunity and Inflammation, Rutgers-New Jersey Medical School, Newark, NJ, USA.
¹² Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland.
¹³ Department of Neuroscience, Università degli Studi di Firenze, Florence, Italy.
¹⁴ Laboratory of Physiologic Studies, Section on Oxidative Stress Tissue Injury, NIAAA, NIH, Bethesda, USA.
¹⁵ Institute of Anesthesiological Pathophysiology and Process Engineering, University Hospital, Ulm, Germany.
¹⁶ Radikal Therapeutics Inc., West Tisbury, MA, USA.
¹⁷ Department of Neurology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
¹⁹ Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
²⁰ Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
²¹ Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
²² Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.

PMID: 28213892
PMCID: PMC5758399
DOI: 10.1111/bph.13748

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.

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Figures

**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.

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References

1. Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006). Minocycline inhibits poly(ADP‐ribose) polymerase‐1 at nanomolar concentrations. Proc Natl Acad Sci U S A 103: 9685–9690. - PMC - PubMed
1. Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010). NAD+ depletion is necessary and sufficient for poly(ADP‐ribose) polymerase‐1‐mediated neuronal death. J Neurosci 30: 2967–2978. - PMC - PubMed
1. Aldinucci A, Gerlini G, Fossati S, Cipriani G, Ballerini C, Biagioli T et al. (2007). A key role for poly(ADP‐ribose) polymerase‐1 activity during human dendritic cell maturation. J Immunol 179: 305–312. - PubMed
1. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024–6109. - PMC - PubMed
1. Ali M, Kamjoo M, Thomas HD, Kyle S, Pavlovska I, Babur M et al. (2011). The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice. Mol Cancer Ther 10: 2320–2329. - PMC - PubMed

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[1] Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006). Minocycline inhibits poly(ADP‐ribose) polymerase‐1 at nanomolar concentrations. Proc Natl Acad Sci U S A 103: 9685–9690. - PMC - PubMed

[2] Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006). Minocycline inhibits poly(ADP‐ribose) polymerase‐1 at nanomolar concentrations. Proc Natl Acad Sci U S A 103: 9685–9690. - PMC - PubMed

[3] Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010). NAD+ depletion is necessary and sufficient for poly(ADP‐ribose) polymerase‐1‐mediated neuronal death. J Neurosci 30: 2967–2978. - PMC - PubMed

[4] Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010). NAD+ depletion is necessary and sufficient for poly(ADP‐ribose) polymerase‐1‐mediated neuronal death. J Neurosci 30: 2967–2978. - PMC - PubMed

[5] Aldinucci A, Gerlini G, Fossati S, Cipriani G, Ballerini C, Biagioli T et al. (2007). A key role for poly(ADP‐ribose) polymerase‐1 activity during human dendritic cell maturation. J Immunol 179: 305–312. - PubMed

[6] Aldinucci A, Gerlini G, Fossati S, Cipriani G, Ballerini C, Biagioli T et al. (2007). A key role for poly(ADP‐ribose) polymerase‐1 activity during human dendritic cell maturation. J Immunol 179: 305–312. - PubMed

[7] Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024–6109. - PMC - PubMed

[8] Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024–6109. - PMC - PubMed

[9] Ali M, Kamjoo M, Thomas HD, Kyle S, Pavlovska I, Babur M et al. (2011). The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice. Mol Cancer Ther 10: 2320–2329. - PMC - PubMed

[10] Ali M, Kamjoo M, Thomas HD, Kyle S, Pavlovska I, Babur M et al. (2011). The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice. Mol Cancer Ther 10: 2320–2329. - PMC - PubMed

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

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

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