Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination

Jones, Philip; Wilcoxen, Keith; Rowley, Michael; Toniatti, Carlo

doi:10.1021/jm5018237

Cited by 125 publications

(111 citation statements)

References 52 publications

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“…In addition, DNA repair pathways fix DNA damage caused by chemotherapeutics, which lead to resistance to these agents. Therefore, targeting DNA repair mechanisms has been successfully explored in cancer drug discovery (Jones et al 2015).…”

Section: Poly(adp-ribose) Polymerase (Parp) Inhibitorsmentioning

confidence: 99%

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Recent Advances and Perspectives in Cancer Drug Design

Magalhães

Ferreira

Andricopulo

2018

An. Acad. Bras. Ciênc.

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Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Several noteworthy advances have been made, among which the development of targeted therapies is the most significant. Monoclonal antibodies and antibody-small molecule conjugates have emerged as a worthwhile approach to improve drug selectivity and reduce adverse effects, which are the main challenges in cancer drug discovery. This review will examine the current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years. Breakthrough discoveries will be highlighted along with the medicinal chemistry strategies used throughout the discovery process. In addition, this review will provide perspectives and updates on the discovery of novel molecular targets as well as drugs with innovative mechanisms of action.

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Section: Poly(adp-ribose) Polymerase (Parp) Inhibitorsmentioning

confidence: 99%

“…Following these findings, PARPs have been studied as molecular targets for cancer, and the pioneer inhibitors in this class entered clinical trials in the 1990s as cytotoxic or ionizing radiation sensitizers. The clinical tests were discontinued because of toxicity issues (Jones et al 2015).…”

Section: Poly(adp-ribose) Polymerase (Parp) Inhibitorsmentioning

confidence: 99%

Recent Advances and Perspectives in Cancer Drug Design

Magalhães

Ferreira

Andricopulo

2018

An. Acad. Bras. Ciênc.

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“…BSI-201 Iniparib (BiPar/Sanofi), used for intravenous administration, was the first inhibitor that has entered Phase III studies and, besides the discrepancies between the phase II and III studies, has shown antitumor activity mostly in combined therapy with gemcitabine and carboplatinum [97–99]. MK-4827 Niraparib (Merck/Tesaro), used for oral administration, is a potent inhibitor of PARP1 and PARP2 and is currently being tested in Phase III clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer [100–102]. BMN-673 (BioMarin), used for oral administration, is more potent than Olaparib and is used in combined therapy in Phase III evaluation [103, 104].…”

Section: Main Bodymentioning

confidence: 99%

Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic

Cerrato

Morra

Celetti

2016

J Exp Clin Cancer Res

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BackgroundDNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects.Main bodyIn this review we discuss the proof of concept for the use of PARPi in different cancer types and the success and failure of their inclusion in clinical trials.The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes. BRCA mutations are now recognised as the molecular targets for PARPi sensitivity in several tumors. However, it is noteworthy that the use of PARPi has shown its efficacy also in non-BRCA related tumors. Several trials are ongoing to test different PARPi in different cancer types. Here we review the concept of BRCAness and the functional loss of proteins involved in DDR/HR mechanisms in cancer, including additional molecules that can influence the cancer cells sensitivity to PARPi. Given the complexity of the existing crosstalk between different DNA repair pathways, it is likely that a single biomarker may not be sufficient to predict the benefit of PARP inhibitors therapies. Novel general assays able to predict the DDR/HR proficiency in cancer cells and the PARPi sensitivity represent a challenge for a personalized therapy.ConclusionsPARP inhibition is a potentially important strategy for managing a significant subset of tumors. The discovery of both germline and somatic DNA repair deficiencies in different cancer patients, together with the development of new PARP inhibitors that can kill selectively cancer cells is a potent example of targeting therapy to molecularly defined tumor subtypes.

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“…123–125 Niraparib (MK-4827) is a PARP-1 and PARP-2 inhibitor that induces cell cycle arrest at the G2/M phase in BRCA1 deficient cells. 126 Combinational treatment of niraparib with ROS induction, like ionizing radiation that requires more DNA repair activity, showed strong synergy. Several other PARP inhibitors are in late stage clinical development.…”

Section: Ros-targeted Anticancer Agentsmentioning

confidence: 99%

Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability

2016

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Although the terms “excessive reactive oxygen species (ROS)” and “oxidative stress” are widely used, the implications of oxidative stress are often misunderstood. ROS are not a single species but a variety of compounds, each with unique biochemical properties and abilities to react with biomolecules. ROS cause activation of growth signals through thiol oxidation and may lead to DNA damage at elevated levels. In this review, we first discuss a conceptual framework for the interplay of ROS and antioxidants. This review then describes ROS signaling using FLT3-mediated growth signaling as an example. We then focus on ROS-mediated DNA damage. High concentrations of ROS result in various DNA lesions, including 8-oxo-7,8-dihydro-guanine, oxazolone, DNA–protein cross-links, and hydantoins, that have unique biological impacts. Here we delve into the biochemistry of nine well-characterized DNA lesions. Within each lesion, the types of repair mechanisms, the mutations induced, and their effects on transcription and replication are discussed. Finally, this review will discuss biochemically inspired implications for cancer therapy. Several teams have put forward designs to harness the excessive ROS and the burdened DNA repair systems of tumor cells for treating cancer. We discuss inhibition of the antioxidant system, the targeting of DNA repair, and ROS-activated prodrugs.

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Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination

Cited by 125 publications

References 52 publications

Recent Advances and Perspectives in Cancer Drug Design

Recent Advances and Perspectives in Cancer Drug Design

Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic

Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability

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