Relevant bibliographies by topics / PARP1 Inhibitors

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Academic literature on the topic 'PARP1 Inhibitors'

Author: Grafiati
Published: 6 September 2023

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Journal articles on the topic "PARP1 Inhibitors"

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Kam, Caleb M., Amanda L. Tauber, Stephan M. Levonis, and Stephanie S. Schweiker. "Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14." Future Medicinal Chemistry 12, no. 24 (December 2020): 2179–90. http://dx.doi.org/10.4155/fmc-2020-0218.

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Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.
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Maluchenko, Natalya, Darya Koshkina, Anna Korovina, Vasily Studitsky, and Alexey Feofanov. "Interactions of PARP1 Inhibitors with PARP1-Nucleosome Complexes." Cells 11, no. 21 (October 23, 2022): 3343. http://dx.doi.org/10.3390/cells11213343.

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Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions of PARP1-nucleosome complexes with PARPi, olaparib (Ola), talazoparib (Tala), and veliparib (Veli) were studied. PARPi trap PARP1 on nucleosomes without affecting the structure of PARP1-nucleosome complexes. The efficiency of PARP1 trapping on nucleosomes increases in the order of Tala>Ola>>Veli, recapitulating the relative trapping efficiencies of PARPi in cells, but different from the relative potency of PARPi to inhibit the catalytic activity of PARP1. The efficiency of PARP1 trapping on nucleosomes correlates with the level of inhibition of auto-PARylation, which otherwise promotes the dissociation of PARP1-nucleosome complexes. The trapping efficiencies of Tala and Ola (but not Veli) are additionally modulated by the enhanced PARP1 binding to nucleosomes. The dissociation of PARP1-nucleosome complexes occurs without a loss of histones and leads to the restoration of the intact structure of nucleosomal DNA. The data suggest that the chromatin structure can considerably affect the efficiency of the PARPi action.
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Zientara-Rytter, Kasia, Veronique T. Baron, Junguk Park, Pavel Shashkin, and Henry Zhu. "Abstract 6111: Design of a small molecule screening assay to detect DNA trapping of PARP1/2." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6111. http://dx.doi.org/10.1158/1538-7445.am2023-6111.

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Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors are currently used in the clinic for the treatment of tumors with a defective DNA damage response (DDR). When PARP1 or PARP2 binds damaged DNA, it adds poly(ADP-ribose) chains to its own backbone and to other DDR proteins, which recruits and activates them. PARylated PARP1/2 next detaches from the DNA so that the other PARylated proteins can initiate the repair process. It has been observed that some PARP inhibitors prevent PARP1/2 from dissociating the DNA. The continuous presence of PARP at the site of damage prevents repair and blocks replication, leading to cell death. Therefore, drugs that trap PARP1/2 to the DNA tend to be significantly more cytotoxic than other PARP inhibitors, which is highly desirable. This study describes the design and optimization of novel PARPtrap assays to specifically assess the ability of a drug to trap PARP onto DNA. The assay is based on principles of fluorescence polarization and uses fluorescently labeled DNA probes that are excited by polarized light and emit light with a degree of polarization that is proportional to the rate of molecular rotation. The free DNA probes that rotate fast have low fluorescence polarization (FP), but high FP when are bound to PARP1 or PARP2. When NAD+ is added, the PARylated enzymes detach from the probe, reducing FP levels. If a PARP inhibitor is added, the inhibitor’s trapping ability increases FP in a dose-dependent manner. Proof-of-principle titration of known PARP-trapping inhibitors (Talazoparib, AZD305, Olaparib and Veliparib) was performed to validate the assay. We observed that: i)The known relative trapping efficacies of Talazoparib, Olaparib and Veliparib were similar to known relative efficacies. ii)Talazoparib, Olaparib and Veliparib had similar trapping efficacy against PARP1 and PARP2, as measured by their EC50, whereas AZD305 was 1,000 times more efficient at trapping PARP1 than it was PARP2, demonstrating selectivity between PARP1 and PARP2. iii)AZD305 displayed as efficient DNA trapping activity toward PARP1 as best-in-class Talazoparib. In summary, we have designed an innovative PARPtrap assay designed for the high throughput screening of small molecule libraries to specifically identify or compare inhibitors that are capable of trapping PARP1 and/or PARP2 onto DNA. Citation Format: Kasia Zientara-Rytter, Veronique T. Baron, Junguk Park, Pavel Shashkin, Henry Zhu. Design of a small molecule screening assay to detect DNA trapping of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6111.
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Ji, Ming, Liyuan Wang, Nina Xue, Fangfang Lai, Sen Zhang, Jing Jin, and Xiaoguang Chen. "The Development of a Biotinylated NAD+-Applied Human Poly(ADP-Ribose) Polymerase 3 (PARP3) Enzymatic Assay." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 6 (April 20, 2018): 545–53. http://dx.doi.org/10.1177/2472555218767843.

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Poly(ADP-ribose) polymerase 3 (PARP3) is an important member of the PARP family and shares high structural similarities with both PARP1 and PARP2. The biological roles of PARP3 are currently under investigation; however, several key reports indicate the integral roles of PARP3 in DNA damage repair, and thus it has been investigated as a novel target in oncology. It is clear that the identification of selective PARP3 inhibitors would further advance the understanding of the biological roles of PARP3. Herein, we describe a modified PARP3 screening assay using biotinylated NAD+ as the specialized substrate. This method relies on the activity of PARP3 to transfer the biotinylated NAD+ onto a histone protein to form ADP-ribosylated histone. The biotin label on this histone protein is then detected and quantifies the intrinsic enzymatic activity of PARP3. We optimized the assay with respect to the histone, NAD+/biotinylated NAD+ mixture, DNA, and PARP3. Our developed screening system was then validated with a reported selective PARP3 inhibitor, ME0328, as well as utilizing five other clinically available PARP1/2 inhibitors. We demonstrated that our assay system was sensitive, efficient, and economical, and we reason that it could be useful for the development of highly selective PARP3 inhibitors in the future.
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Halazonetis, Thanos D., Michalis Petropoulos, Giacomo G. Rossetti, Angeliki Karamichali, Alena Freudenmann, Luca Iacovino, Vasilis Dionellis, and Sotirios K. Sotiriou. "Abstract 1566: DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1566. http://dx.doi.org/10.1158/1538-7445.am2023-1566.

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Abstract An important advance in cancer therapy in the last decade has been the development of poly ADP-ribose polymerase (PARP) inhibitors for the treatment of select ovarian and breast cancers. The clinical benefit stems from the synthetic lethality of PARP inhibitors with homologous recombination (HR) deficiency, which deficiency is prevalent in the cancer types listed above. The current model to explain the synthetic lethality is based on the observation that PARP inhibitors trap PARPs on DNA: the trapped PARPs block progression of the replisome, leading to the formation of DNA double-strand breaks (DSBs), which require HR for repair. Here, we propose a novel mechanism to explain the synthetic lethality between PARP inhibitors and HR deficiencies. We show that PARP1 functions together with the proteins TIMELESS and TIPIN to protect the replisome from transcription-replication conflicts (TRCs). In the absence of any one of these proteins, TRCs evolved into DNA DSBs that required HR for repair, explaining the observed synthetic lethality. In further support of this model, when we inhibited transcription elongation, which prevents the emergence of transcription-replication conflicts, then the HR-deficient cancer cells became resistant to PARP inhibitors. We further observed that trapping of PARPs on DNA was not required for the synthetic lethality with HR deficiency, since we could observe strong synthetic lethality simply by depleting PARP1 and PARP2 by siRNA. Rather, trapping of PARPs on DNA correlated with the ability of the various PARP inhibitors to inhibit PARP enzymatic activity in cells; the strongest trappers were also the most potent inhibitors of PARP1 in cells. In vitro, all PARP inhibitors tested were almost equipotent in their ability to inhibit the enzymatic activity of PARP1, meaning that the potency of PARP1 inhibitors in vitro did not reflect their inhibitory potency in cells. Our model provides a new framework for understanding the mechanism of action of PARP inhibitors in the clinic and the mechanisms by which resistance can emerge. Citation Format: Thanos D. Halazonetis, Michalis Petropoulos, Giacomo G. Rossetti, Angeliki Karamichali, Alena Freudenmann, Luca Iacovino, Vasilis Dionellis, Sotirios K. Sotiriou. DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1566.
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Wang, Kai, Yizhou Wu, Lizhu Lai, Xin Wang, and Shuya Sun. "How ligands regulate the binding of PARP1 with DNA: Deciphering the mechanism at the molecular level." PLOS ONE 18, no. 8 (August 15, 2023): e0290176. http://dx.doi.org/10.1371/journal.pone.0290176.

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The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.
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Yin, Ling, and Junjie Chen. "Abstract 6098: Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6098. http://dx.doi.org/10.1158/1538-7445.am2023-6098.

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Abstract The first-generation PARP inhibitors (PARPi) olaparib, niraparib, talazoparib and rucaparib have been clinically approved for several cancers, like breast, ovarian and prostate, especially in BRCA-mutant tumors which are of homologous recombination repair (HRR)-deficiency. All PARPi both target PARP1 and PARP2, causing cancer cell deaths deficient in HRR. However, only inhibition of PARP1 is required for synthetic lethality in HRR-deficient cells. AZD5305 is a highly selective PARP1 inhibitor which has been used in clinical trials. In this study, we used the Toronto Knock Out Library version 3 (TKOv3), which contains 70948 gRNAs targeting 18,053 protein-coding genes to perform whole-genome CRISPR-Cas9 screens with three isogenic cell lines 293A, MCF10A, and Hela to uncover known and new high-confidence genes synthetic lethal interacted with AZD5305. MAGeCK and Drug Z were used to analyze the results and genes were ranked according to their drugZ scores. We identify that in all three cell lines, PARP1 was in the top hit in positive selection which proves the AZD5305 indeed a PARP1 inhibitor. Moreover, through a comprehensive and comparative analysis with the screen results of first generation PARPi olaparib, we reveal known and new essential genes which are proved to be a common mechanism for synthetic lethality. We identify the gene AUNIP (Aurora Kinase A and Ninein Interacting Protein), in the top hit from AZD5305 screen but not in olaparib screen, suggesting that AUNIP may be an additional target for synthetic lethality with PARP1 loss. Taken together, this screen reveals the potential molecular genes related with PARP1 inhibitor that can be further explored targeted and combined cancer therapy. Citation Format: Ling Yin, Junjie Chen. Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6098.
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Krastev, Dragomir B., Andrew J. Wicks, and Christopher J. Lord. "PARP Inhibitors – Trapped in a Toxic Love Affair." Cancer Research 81, no. 22 (November 15, 2021): 5605–7. http://dx.doi.org/10.1158/0008-5472.can-21-3201.

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Abstract It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination–defective cancers. In 2012, nearly a decade after the first PARPi entered clinical development, work from Murai and colleagues demonstrated that clinical PARPi not only inhibit the catalytic activity of PARP1, PARylation, but also “trap” PARP1 on DNA; this latter effect being responsible for much of the tumor cell cytotoxicity caused by these drugs. We discuss how this work not only changed our understanding about how PARPi work, but also stimulated subsequent dissection of how PARP1 carries out its normal function in the absence of inhibitor. See related article by Murai and colleagues, Cancer Res 2012;72:5588–99
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Nieborowska-Skorska, Margaret, Paulina Podszywalow-Bartnicka, Silvia Maifrede, Bac Viet Le, Monika Toma, Peter Valent, Tomasz Sliwinski, et al. "PARP1 Inhibitors Eliminated Imatinib-Refractory Chronic Myeloid Leukemia Cells in Bone Marrow Microenvironment Conditions." Blood 132, Supplement 1 (November 29, 2018): 3000. http://dx.doi.org/10.1182/blood-2018-99-115041.

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Abstract Bone marrow microenvironment (BMM) also defined as a stem cell niche provides a major obstacle for current anti-leukemia treatment modalities including tyrosine kinase inhibitors (TKIs) such as imatinib. We recently reported that chronic myeloid leukemia (CML) stem cells are sensitive to PARP inhibitor (PARPi)-triggered synthetic lethality in conditions mimicking peripheral blood (normoxia, no stromal cells). We reported that PARPi olaparib and talazoparib eliminate imatinib-refractory CML cells in the conditions mimicking BMM (hypoxia, stromal cells present). The effect, however, is not as robust as that observed in normoxia implicating BMM-specific protective impact. Therefore, more efficient targeting of PARP is required to enhance synthetic lethal effect against CML in BMM. Most PARPi's have been designed to compete with NAD for a binding site on the PARP1 molecule. This strategy resulted in the discovery of nucleotide-like PARPi's that not only target PARP, but, unfortunately, other enzymatic pathways involving NAD and other nucleotides as co-factors. Using such inhibitors affects multiple NAD/nucleotide-dependent enzymatic pathways, which results in secondary toxic effects proceeding from the inactivation of other pathways, while the efficiency against the PARP pathway is diminished. Thus, the challenge is to design inhibitors based on other activities of PARP1. We reported that DSBs-dependent interaction of PARP1 with histone 4 (H4) resulted in activation of PARP1 enzymatic activity and stimulation of Alt-NHEJ. Using high-throughput screen we identified non-NAD-like inhibitors, which interfered with H4-mediated activation of PARP1 and were effective against several types of tumors including BRCA1-deficient CML cells. Here we show that combination of two structurally different PARPi's, NAD-like olaparib or talazoparib and non-NAD-like 5F02 resulted in more abundant elimination of CML cells and reduced toxicity to normal counterparts. Finally, the combination exerted synergistic effect in humanized immunodeficient mice bearing primary CML xenografts. Altogether, non-NAD-like PARP1i synergistically enhanced synthetic lethal effect of NAD-like PARPi in tumor cells without increasing the cytotoxic effect in normal cells. While synthetic lethality mediated by NAD-like PARPi is usually associated with enhanced accumulation of potentially lethal DSBs, non-NAD-like PARP1i 5F02 did not induce DSBs when used as a single agent and also in combination with olaparib. Thus, the mechanistic aspect of the synergistic effect of NAD-like and non-NAD-like PARPis needs to be elucidated. Nevertheless, our data suggest that combining NAD-like and allosteric non-NAD-like PARPi's may represent a viable therapeutic strategy for enhancing CML response to PARP inhibition and reducing the resistance that inevitably results from treatment with NAD-like PARPi's alone. Disclosures Valent: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.
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Tutt, Andrew. "Abstract ED12-3: ATR inhibitors and PARP1 selective PARP inhibitors." Cancer Research 83, no. 5_Supplement (March 1, 2023): ED12–3—ED12–3. http://dx.doi.org/10.1158/1538-7445.sabcs22-ed12-3.

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Abstract The targeting of Homologous Recombination deficient (HRD) malignancy using a synthetic lethal strategy based on the inhibition and trapping of PARP1 on DNA in manner that leads to tumour selective effects via dependency on the function of HR gene products such as BRCA1, BRCA2 and PALB2 for DNA replication fitness is now well established. However, there is a need to improve both the frequency and duration of response in the licensed indications and to explore combination PARP inhibitor (PARPi) strategies that may be effective a broader range of breast cancers with functional deficiencies in HR and the wider DNA damage response. ATR inhibitors exacerbate replication stress that is toxic to HR deficient cells. Combinations of an ATR inhibition (ATRi) and PARPi have been shown to be synergistic and to be active in PARPi resistant pre-clinical model contexts. The development of combination strategies of these agents and of platinums and ATRi have been limited by combinatorial toxicity but have recently reported results in breast cancer. PARP1 is part of a family of PARP enzymes and currently licensed PARPi inhibit several family members that underpin some of their toxicity. New PARP1 selective agents have recently reported results in early phase trials. I will review some of the mechanistic rationale, preclinical data and relevant clinical trial data in my lecture. Citation Format: Andrew Tutt. ATR inhibitors and PARP1 selective PARP inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED12-3.
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Dissertations / Theses on the topic "PARP1 Inhibitors"

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Alkhateeb, Hebah, Gregory A. Ordway, W. Drew Gill, Joshua B. Coleman, Hui Wang-Heaton, Russell W. Brown, Michelle Chandley, et al. "PARP1 inhibition produces unique antidepressant effects in an animal model of treatment-resistant depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/49.

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Major depressive disorder (MDD) is a prevalent and enervating mental illness affecting millions globally. Unfortunately, a significant proportion of patients do not receive clinical benefit from existing antidepressant medications. The limited effectiveness of currently available antidepressant drugs emphasizes the need to identify more effective medications for individuals who are treatment-resistant. We have previously reported abnormally elevated poly (ADP-ribose) polymerase-1 (PARP1) gene expression levels in the postmortem brain from MDD brain donors. PARP1 is a DNA damage repair enzyme that is also linked to neuroinflammation through multiple biochemical pathways. PARP1 upregulation in MDD could indicate a role for this enzyme in the etiopathology of MDD, particularly as it relates to neuroinflammation. In fact, we have shown that drugs that inhibit PARP1 produce antidepressant-like properties in two different rodent behavioral models that mimic depressed mood in humans. In the present study, we utilized a unique rodent behavioral model that produces depressive-like behavior by combining psychological stress with stimulation of inflammation. Depressive behavior produced by this experimental paradigm is not reversed by the prototypical antidepressant fluoxetine. This treatment-resistant depression was elicited by treating rats with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily exposure to chronic unpredictable stress (CUS) for 28 days. Depressive behaviors were measured with sucrose preference and forced swim tests in 5 treatment groups (n=6-8 rats per group) including unstressed rats, CUS rats, CUS+LPS rats, and CUS+LPS rats treated with either the PARP1 inhibitor 3-aminobenzamide (3AB) or the antidepressant fluoxetine. We evaluated the role of neuroinflammation in this model by measuring the amount of microglial activation in several brain regions in rats from all treatment groups. Microglia activation was measured by quantifying the relative amount of expression of the microglia marker protein, IBA1, using an anti-IBA1 antibody. 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the treatment-resistant rat model. IBA1-immunoreactivity levels were elevated in brains from CUS and CUS+LPS rats, although there was no evidence that LPS increased IBA1-immunoreactivity above levels found in CUS rats that did not receive LPS. Levels of IBA1-immunoreactivity in the brains from rats treated with either fluoxetine or 3AB trended lower as compared to the CUS and CUS+LPS groups, although this effect did not reach statistical significance. The lack of significant differences is likely related to small sample sizes; experiments are underway to increase the sample sizes of each group. The findings provide further support for the potential of PARP1 inhibitors in treating MDD and suggest that these drugs may be more effective, or more broadly effective than standard antidepressants.
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D'Angeli, Floriana. "Biomolecular effects and bioclinical applications of PARPs inhibitors." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/3832.

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Abstract Section I Inhibitors of PARP-1(Poly(ADP-ribose) polymerase-1) act by competing with NAD+, the enzyme physiological substrate, which play a protective role in many pathological conditions characterized by PARP-1 overactivation. It has been shown that PARP-1 also promotes tumor growth and progression through its DNA repair activity. Since angiogenesis is an essential requirement for these activities, we sought to determine whether PARP inhibition might affect rat brain microvascular endothelial cells (GP8.3) migration, stimulated by C6-glioma conditioned medium (CM). Through wound-healing experiments and MTT analysis, we demonstrated that PARP-1 inhibitor PJ-34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide] abolishes the migratory response of GP8.3 cells and reduces their viability. PARP-1 also acts in a DNA independent way within the Extracellular-Regulated-Kinase (ERK) signaling cascade, which regulates cell proliferation and differentiation. By western analysis and confocal laser scanning microscopy (LSM), we analysed the effects of PJ-34 on PARP-1 expression, phospho-ERK and phospho-Elk-1 activation. The effect of MEK (mitogen-activated-protein-kinase-kinase) inhibitor PD98059 (2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) on PARP-1 expression in unstimulated and in CM-stimulated GP8.3 cells was analyzed by RT-PCR. PARP-1 expression and phospho-ERK activation were significantly reduced by treatment of GP8.3 cells with PJ-34 or PD98059. By LSM, we further demonstrated that PARP-1 and phospho-ERK are coexpressed and share the same subcellular localization in GP8.3 cells, in the cytoplasm as well as in nucleoplasm. Based on these data, we propose that PARP-1 and phospho-ERK interact in the cytosol and then translocate to the nucleus, where they trigger a proliferative response. We also propose that PARP-1 inhibition blocks CM-induced endothelial migration by interfering with ERK signal-transduction pathway.
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Geraets, Liesbeth. "Dietary PARP-1 inhibitors as anti-inflammatory compounds." Maastricht : Maastricht : Universitaire Pers ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=14252.

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Kumpan, Katerina. "Structure-activity studies on inhibitors of the tankyrases." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619223.

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Tankyrases-1 and -2 (TNKS-1 and -2) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily, which modify and regulate target proteins by addition of multiple (ADP-ribose) units from the substrate NAD+. TNKS-1 and -2 have many cellular roles, including regulation of elongation of telomeres, activation of nuclear mitotic apparatus protein (NuMA) in mitosis and regulation of the Wnt signalling pathway. This makes the tankyrases attractive new targets for design and development of new anti-cancer drugs. 2-(4-Trifluoromethylphenyl)-7,8-dihydro-3H-thiopyranopyrimidin-4-one (XAV939) was one of the few active inhibitors of tankyrases reported until 2013. The aim of this project was to explore the structure-activity relationships towards enhancing potency and selectivity by replacing the saturated sulfur-containing ring with saturated and unsaturated nitrogen heterocycles and by varying the aromatic side-chain. Firstly, ascorbate-modified Sonogashira couplings of bromocyanopyridines and a variety of 4-substituted arylethynes, followed by acidic cyclisation and conversion of the lactone into the lactam, gave differently substituted arylnaphthyridinones. The alternative route used transition-metal-free reaction of bromopyridinecarboxylic acids with symmetrical β-diketones. 7-Phenyl-1,6-naphthyridin-5-one and 7-(4-methylphenyl)-1,6-naphthyridin-5-one were converted to the N1-oxides. Alkylation at 1-N gave 7-aryl-1-methyl-5-oxo-5,6-dihydro-1,6-naphthyridin-1-ium iodides and subsequent reduction gave saturated target 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Other target compounds included pyridopyrimidinones, which were prepared from the corresponding bromopyridinecarboxylic acids by a copper-catalysed reaction with 4-substituted benzamidines. Target tetrahydropyridopyrimidinones, however, were obtained from condensation of 1-benzyl-4-oxopiperidine-3-carboxylic esters with substituted benzamidines. All compounds were evaluated in vitro for inhibition of the catalytic activity of TNKS-2. The best compounds were investigated further, including in vitro TNKS-1 and PARP-1 inhibition and anti-proliferative studies on HT29 and FEK4 cell lines. Notably, 1-methyl-7-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one and 1-methyl-7-(4-methoxyphenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one showed 50% inhibition of TNKS-2 at 1.5 nM and 1.1 nM, respectively, showing also high selectivity (IC50 against PARP-1: 4.8 μM and 3.4 μM, respectively). This high potency and selectivity point to potential for development towards therapeutic use in cancer. A patent covering these discoveries has been filed.
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Ahmed, Zina. "Poly-ADP ribos polymeras (PARP) inhibitorers effekt på bröstcancer : Poly-ADP ribos polymeras (PARP) inhibitorers effekt på bröstcancer." Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-103397.

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Almeida, Gilberto Serrano de. "Pre-clinical imaging evaluation of the PARP inhibitor rucaparib." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2033.

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Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA-binding enzyme involved in DNA repair by the base-excision pathway. The inhibition of PARP1 is being investigated as a cancer treatment. Rucaparib (CO338) is a potent PARP 31 inhibitor currently in Phase II clinical development. In this thesis P in vivo MR Spectroscopy (MRS) and Dynamic Contrast Enhanced (DCE) MRI were used to study acute effects of rucaparib on energy metabolism and tumour vasculature. 1 31 18 18 Ex vivo H and P-MRS, and in vivo [ F]FLT and [ F]FDG-PET, were used to study effects of treatment with rucaparib on tumour metabolism and proliferation. A2780 and SW620 tumours implanted in mice were scanned in a horizontal Varian 7T MR system. Two i.v. injections of the MRI contrast agent gadoteridol were given 90 minutes apart with dynamic phosphorus MRS acquired following the injection of rucaparib, temozolomide or both drugs in combination. The 18 18 same tumours were evaluated by [ F]FLT- and [ F]FDG-PET after 5 daily treatments with rucaparib, temozolomide or the combination, and the livers of PARP1 knock out (KO) and wild type (WT) mice treated in a similar manner 1 31 were analysed by ex vivo H and P-MRS. Tumour uptake of gadoteridol changed significantly after treatment with hydralazine and higher doses of rucaparib in SW620 tumours, and following 31 hydralazine and 1mg/Kg of rucaparib in A2780 tumours. P-MRS studies revealed an increase in the inorganic phosphate (Pi) to β-NTP ratio, consistent with impairment of tumour energy metabolism following hydralazine treatment. 18 [ F]FLT-PET demonstrated a significant reduction in the SUV values in the 18 rucaparib/temozolomide combination group in SW620 tumours, and [ F]FDG- PET revealed a non-significant reduction in tumour metabolism in A2780 1 tumours. H ex vivo MRS demonstrated an increase in the liver NAD concentrations after treatment with rucaparib, but a decrease following the treatment with temozolomide, regardless of the PARP1 status. Together, these pre-clinical imaging studies have shown that MR can be used 18 to investigate the acute anti-vascular effects of rucaparib, that [ F]FLT-PET predicted subsequent changes in tumour volume following combined rucaparib 1 and temozolomide treatment, and that ex vivo H-MRS can be used in mechanistic studies of PARP inhibition. Both MRI/MRS and PET are potential pharmacodynamic and surrogate response imaging biomarkers for PARP inhibitors.
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Hukkanen, M. (Mikko). "DNA damage sensitization of breast cancer cells with PARP10/ARTD10 inhibitor." Master's thesis, University of Oulu, 2019. http://jultika.oulu.fi/Record/nbnfioulu-201909062843.

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Abstract. In this thesis, I studied the DNA damage sensitization of breast cancer cells with PARP10/ARTD10 inhibitor. As the ARTD10 inhibition field is relatively fresh, tests with breast cancer cell lines combined with clinically used chemotherapeutics will elucidate the potential future uses of the inhibitors in a clinically relevant context, directing the future research efforts in the field. To study the link between OUL35 and DNA damage sensitization, cell proliferation experiments were conducted, and to determine whether ARTD10 translocation from cytoplasm into nucleus is enhanced under DNA damaging conditions, western blot assay was performed. Also, the OUL35 potency against full-length ARTD10 was verified to compare it with the catalytic ARTD10 fragment. The determined IC50 of 510 nM suggests that the potency does not differ from studies with catalytic domain. According to the results from ARTD10 translocation studies, it can only be said that DNA damaging agent in general reduces the amount of cytoplasmic ARTD10, whereas I could not confirm the potential translocation to the nucleus. The results of OUL35-mediated sensitization to DNA damaging agents indicates that OUL35 might sensitize breast cancer cells to DNA damage. As a summary, full-length ARTD10 inhibition does not vary from catalytic domain, suggesting that either construct can be used for testing inhibitors, OUL35 may enhance the effect of other DNA damaging agents, and there is a possibility that HU might have an influence on the nuclear translocation of ARTD10. This provides the basis for future evaluation of larger cancer cell panels for sensitization for chemotherapeutics by ARTD10 inhibition.
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Castroviejo, Bermejo Marta. "RAD51 as functional biomarker to select tumors for PARP inhibitor treatment." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667273.

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Los inhibidores de la enzima Poly (ADP-ribosa) polimerasa (PARPi) son efectivos en el tratamiento de cánceres que presentan defectos en la reparación del ADN por recombinación homóloga (HRR), incluyendo aquellos con mutaciones en BRCA1 y BRCA2 (BRCA1/2). Se han descrito distintos mecanismos de resistencia a PARPi en tumores con mutaciones germinales en BRCA1/2 (gBRCA), y existen otros tumores sin mutaciones en BRCA1/2 (no-BRCA) que responden a PARPi. Existe la necesidad de desarrollar un biomarcador robusto para una mejor selección de tumores deficientes en HRR y extender el uso de PARPi a nuevas indicaciones, así como estudiar terapias en combinación que mejoren la eficacia en la clínica. En este trabajo se evaluó la actividad del PARPi olaparib en xenoimplantes de tumores derivados de pacientes (PDX, patient derived tumor xenografts) con cáncer de mama u ovario, tanto gBRCA como no-gBRCA. Se estudiaron los mecanismos de resistencia y sensibilidad a PARPi in vivo, así como la utilidad de una inmunofluorescencia para detectar focos nucleares de RAD51 como biomarcador de HRR y respuesta a PARPi, tanto en PDXs como en muestras clínicas. Además, se investigó la actividad antitumoral del inhibidor de WEE1 AZD1775 y del inhibidor de ATM AZD0156 en monoterapia y combinación con PARPi. Se investigaron los mecanismos de acción de estas terapias utilizando distintos marcadores de estrés replicativo. Entre los modelos PDX gBRCA resistentes a PARPi no se encontraron mutaciones secundarias en BRCA1/2 pero sí la formación de focos nucleares de BRCA1, en concordancia con la expresión de proteínas BRCA1 hipomórficas. En tres PDX resistentes a PARPi se identificó la pérdida de 53BP1 y FAM35A como mecanismo de resistencia. La única característica común a todos los PDXs resistentes a PARPi, ya sea resistencia primaria o adquirida, fue la capacidad de formación de focos nucleares de la proteína RAD51. De acuerdo con estos resultados, la ausencia de focos de RAD51 se asoció con respuesta clínica a PARPi en muestras de pacientes. Cuando se estudiaron los mecanismos de sensibilidad a PARPi en la colección de PDXs no-gBRCA, se observó la presencia de hipermetilación del promotor de BRCA1 y alteraciones en otros genes relacionados con HRR en modelos sensibles a PARPi. Sin embargo, de nuevo la única característica común a todos los PDXs respondedores fue la ausencia de focos nucleares de RAD51. El ensayo de RAD51 se pudo realizar en muestras no tratadas y mostró ser altamente discriminativo entre sensibilidad y resistencia a PARPi, superando la capacidad predictiva del test genético myChoice® HRD de Myriad. En muestras clínicas de rutina procedentes de pacientes con síndrome de cáncer de mama y ovario hereditario, todos los tumores relacionados con mutaciones en PALB2 se clasificaron como deficientes en HRR. Finalmente, se demostró que la resistencia a la terapia con PARPi en tumores con alteraciones en BRCA1 puede revertirse combinando estos agentes con un inhibidor de WEE1 o de ATM, y en ambas estrategias se reportó una mayor inducción de estrés replicativo en PDX sensibles a la combinación. Los resultados de esta tesis permiten concluir que los tumores gBRCA logran la resistencia a PARPi mediante diferentes mecanismos que restauran HRR y puede detectarse por la formación de focos nucleares de RAD51. Este ensayo funcional permite identificar tumores no-BRCA sensibles a PARPi y representa un biomarcador prometedor para mejorar la selección de pacientes y ampliar la población candidata a recibir esta terapia. Los resultados también impulsan el desarrollo clínico de estrategias terapéuticas que combinen los PARPi con inhibidores de WEE1 y ATM, destacando la inducción de estrés replicativo como principal mecanismo de acción de estos fármacos.
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective anticancer drugs in cancers with defective homologous recombination DNA repair (HRR), including cancers with mutations in BRCA1 and BRCA2 (BRCA1/2), which also display enhanced sensitivity to DNA damaging chemotherapy such as platinum salts. Several mechanisms of PARPi resistance have been described in tumors with germline mutations in BRCA1/2 (gBRCA) and there are also other tumors with wild type BRCA1/2 (non-BRCA) that benefit from PARPi treatment. Therefore, there is a need to develop robust biomarkers to better select HRR- deficient tumors and extend the use of PARP inhibition in new indications, as well as identify PARPi-resistant tumors and study combination treatment options that enhance clinical efficacy and utility of PARPi. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from patients with breast or ovarian cancer, both with and without gBRCA mutation, exhibiting differential response to PARPi. We studied the in vivo mechanisms of PARPi resistance and sensitivity in these models and tested the formation of RAD51 nuclear foci by immunofluorescence as biomarker of HRR functionality and PARPi response in PDXs and routine clinical samples. We also tested the antitumor activity of the WEE1i AZD1775 and the ATMi AZD0156 as single agent and in combination with PARPi in PDXs. The measurement of replication stress biomarkers was assessed to study the mechanisms of action of these treatment strategies. Within the gBRCA PDXs panel, no BRCA1/2 secondary mutations were found in the PARPi resistant models. BRCA1 nuclear foci were detected in six out of ten PARPi-resistant PDXs, in keeping with expression of hypomorphic BRCA1 isoforms. Loss of 53BP1 and FAM35A were identified in three PDXs, one of which concomitantly expressed an hypomorphic BRCA1 protein. The common feature in all PDXs with primary or acquired PARPi resistance was the formation of RAD51 nuclear foci. Consistently, lack of RAD51 foci was always associated with clinical response to PARPi in patients treated with these agents. When studying the mechanisms of PARPi sensitivity in the non-gBRCA PDX cohort, BRCA1 promoter hypermethylation and alterations in HRR-related genes were found in PARPi- sensitive models. Again, the unique common feature in all PDXs that exhibited tumor regression upon PARPi treatment is the absence of RAD51 nuclear foci. The RAD51 assay could be performed in untreated samples and was highly discriminative of PARPi sensitivity versus PARPi resistance in different PDX cohorts and outperformed the Myriad’s myChoice® HRD genomic test. In routine clinical samples from patients with hereditary breast and ovarian cancer (HBOC) syndrome, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. In PDXs, PARPi resistance in BRCA1-altered tumors could be reverted upon combination of PARPi with WEE1 or ATM inhibitors and both combination strategies resulted in exacerbated induction of replication stress (RS) in combination- sensitive PDXs. With the results obtained in this thesis, it can be concluded that gBRCA tumors achieve PARPi resistance by several mechanisms that restore HRR function, all detected by the presence of RAD51 nuclear foci. This functional assay also enables the identification of PARPi-sensitive non-gBRCA tumors independently of the mechanisms of HRR-deficiency, thereby being a promising biomarker to better select patients for PARP inhibition and broaden the population who may benefit from this therapy. Our study also supports the clinical development of PARPi combinations such as those with WEE1 and ATM inhibitors and highlighted the induction of RS as the major mechanisms of action of these drugs.
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Löser, Dana A. "Investigating the mechanisms by which PARP inhibitors increase sensitivity to DNA damaging agents." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505912.

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Damage induced by ionising radiation (IR) is mainly repaired by classical non homologous end joining (D-NHEJ), but a small subset of DSBs is repaired with slow kinetics in an ATM (Ataxia telangiectasia mutated) and Artemis dependent manner. In addition, a PARP-1 dependent NHEJ backup pathway (B-NHEJ) was described, which is thought to function in the absence of D-NHEJ. Using ATM, Artemis or DNA ligase IV deficient mouse embryonic fibroblasts (MEFs) as a model system, the effect of the potent and specific PARP-1/-2 inhibitor KU-0059436 upon clonogenic survival after various types of damage that induce different spectra of SSBs and DSBs was measured. In Artemis or ATM deficient MEFs no sensitising effect of KU-0059436 was detected after neocarzinostatin (NCS) treatment; however PARP inhibition increased sensitivity to IR and methylmethane sulphonate (MMS) markedly. In these cell lines no specific single strand break repair (SSBR) defect was observed, and radio-sensitisation by KU-0059436 was replication dependent. Furthermore PARP inhibition led to increased formation of DSBs, an effect which was augmented in Artemis deficient cells. PARP inhibition in DNA ligase IV deficient cells led to increased sensitivity after damage induction to all agents. However, radiosensitisation by KU-0059436 was replication independent. Results show that PARP inhibition increases the dependence on Artemis and ATM after SSB induction, which is consistent with a model whereby DSBs that arise from SSBs during DNA replication in the presence of a PARP inhibitor require ATM and Artemis for their repair. In cells deficient for DNA ligase IV, PARP inhibition causes additional replication independent sensitisation both by abrogating B-NHEJ and promoting accumulation of replication independent DSBs.
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Guillot, Clément. "Potentiel des inhibiteurs de poly(ADP-ribose) polymérases seuls ou en combinaison avec la radiothérapie comme nouvelle option thérapeutique pour le carcinome hépatocellulaire." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10281.

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Le carcinome hépatocellulaire est l'un des cancers les plus fréquents et des plus sévères à travers le monde. Le diagnostic est souvent tardif et les traitements curatifs ne peuvent être proposés qu'à un nombre limité de patients. Les technologies modernes ont permis le développement de nouvelles méthodes de radiothérapie qui montrent aujourd'hui de bons résultats. Par ailleurs, bien que des déficiences dans les voies de réparation de l'ADN soient associées à une instabilité génomique et une susceptibilité au cancer, une inhibition de ces voies sensibilise les cellules cancéreuses à la chimiothérapie et à la radiothérapie. Dans ce contexte, les inhibiteurs de poly(ADP-ribose) polymérases (PARP) ont déjà montré des résultats prometteurs dans des études pré-cliniques et sont en cours d'évaluation clinique pour de nombreux cancers. Ce travail de thèse a consisté en l'évaluation du potentiel des inhibiteurs de PARP en combinaison avec la radiothérapie comme nouvelle option thérapeutique pour le carcinome hépatocellulaire. La première étape de ce travail a été de caractériser les profils d'expression et d'activité de plusieurs membres de la famille PARP dans des cellules cancéreuses du foie et des hépatocytes primaires humains ainsi que dans des tissus hépatiques. En second lieu, nous avons étudié le potentiel de l'inhibiteur de PARP ABT-888 seul et en combinaison à des radiations ionisantes in vitro. Le traitement par l'inhibiteur de PARP ABT-888 en agent seul a montré une sensibilité variable des différentes lignées cellulaires étudiées à cette drogue. Afin de comprendre la sensibilité variable des cellules cancéreuses hépatiques à l'ABT-888, nous avons analysé leur capacité de réparation des dommages à l'ADN et avons observé des capacités différentes entre les lignées cellulaires. Finalement, nous avons pu montrer que l'ABT-888 sensibilise les cellules cancéreuses hépatiques aux radiations ionisantes. Ce travail de recherche a permis de montrer que les inhibiteurs de PARP ont un fort potentiel pour améliorer les méthodes de radiothérapie utilisées dans la prise en charge du carcinome hépatocellulaire
Hepatocellular carcinoma is the third cause of cancer related death. Due its often late diagnosis and advanced stage, a limited number of patients can benefit from curative treatments. There is thus a constant need for new treatment strategies for patients with hepatocellular carcinoma. Targeting DNA repair pathways to sensitize tumor cells to chemoor radiotherapeutic treatments is now a common strategy under investigation for cancer treatment with inhibitors of poly(ADP-ribose) polymerases (PARP) showing great potential. The aim of this work was to evaluate the potential of PARP inhibitors alone and in combination with radiation therapy as a new strategy for the treatment of hepatocellular carcinoma. We first analyzed the expression and activity of different PARP genes in a panel of liver cancer cell lines and primary human hepatocytes as well as their DNA repair capacity and assess the impact of PARP inhibitors alone and in combination with ionizing radiation in these models on cell survival. A large range in expression of PARP family members, PARP activity and sensitivity to ABT-888 in the panel of liver cells was observed as well as differential excision/synthesis repair capacity. Finally, we showed that ABT-888 sensitizes liver cancer cells to the cell killing effects of ionizing radiation. PARP inhibitors show great potential for improving radiation therapy strategies used in the management of hepatocellular carcinoma
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Books on the topic "PARP1 Inhibitors"

1

Curtin, Nicola J., and Ricky A. Sharma, eds. PARP Inhibitors for Cancer Therapy. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0.

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Curtin, Nicola J., and Ricky A. Sharma. PARP Inhibitors for Cancer Therapy. Humana, 2018.

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Curtin, Nicola J., and Ricky A. Sharma. PARP Inhibitors for Cancer Therapy. Springer International Publishing AG, 2015.

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Curtin, Nicola J., and Ricky A. Sharma. PARP Inhibitors for Cancer Therapy. Humana Press, 2015.

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Zhang, Jei. PARP As a Therapeutic Target. Taylor & Francis Group, 2002.

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Zhang, Jei. PARP As a Therapeutic Target. Taylor & Francis Group, 2002.

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Hodgkiss, Andrew. Psychiatric consequences of cancer treatments: ‘small molecule’ molecularly targeted agents. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198759911.003.0008.

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The psychiatric consequences of a range of small-molecule, molecularly targeted systemic treatments for cancer are reviewed. Psychopathology may arise from the endocrine complications of VEGFR/multiple TK inhibitors. The mechanisms by which PI3K/AKT inhibition and proteasome inhibition can provoke anxiety and depressive phenomena in animals and humans are discussed. PARP-1 inhibition impairs memory acquisition in animal models and is neuroprotective. PARP-2 inhibitors display anti-neuroinflammatory properties in mice. The cognitive enhancing, mood stabilizing, and neuroprotective effects of HDAC inhibitors are considered.
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PARP as a Therapeutic Target (Handbooks in Pharmacology and Toxicology). CRC, 2002.

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Curtin, Nicola, and Péter Bay, eds. PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer. MDPI, 2023. http://dx.doi.org/10.3390/books978-3-0365-8157-6.

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Book chapters on the topic "PARP1 Inhibitors"

1

Kotova, Elena, Aaron D. Pinnola, and Alexei V. Tulin. "Small-Molecule Collection and High-Throughput Colorimetric Assay to Identify PARP1 Inhibitors." In Methods in Molecular Biology, 491–516. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-270-0_29.

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Priyancy, J., and D. P. Bhumika. "Design and Synthesis of Novel Poly ADP-ribose Polymerase 1 (PARP1) Inhibitors for the Treatment of Solid Tumors." In Special Publications, 31–35. Cambridge: Royal Society of Chemistry, 2019. http://dx.doi.org/10.1039/9781839160783-00031.

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Schwab, Manfred. "PARP Inhibitors." In Encyclopedia of Cancer, 1. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_4395-2.

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Mateo, Joaquin, Timothy A. Yap, and Johann S. De Bono. "PARP Inhibitors." In Management of Castration Resistant Prostate Cancer, 253–64. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1176-9_18.

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Dearman, Charles, Ricky A. Sharma, and Nicola J. Curtin. "Biomarkers for PARP Inhibitors." In Cancer Drug Discovery and Development, 553–79. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_24.

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Daugherty, Larry C., Brandon J. Fisher, Christin A. Knowlton, Michelle Kolton Mackay, David E. Wazer, Anthony E. Dragun, James H. Brashears, et al. "PARP Inhibitors (Poly(ADP-Ribose) Polymerase Inhibitors)." In Encyclopedia of Radiation Oncology, 611. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-540-85516-3_752.

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McCrudden, Cian M., and Kaye J. Williams. "The Vasoactivity of PARP Inhibitors." In Cancer Drug Discovery and Development, 299–311. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_12.

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Shalinsky, David R., Cherrie K. Donawho, Gerrit Los, and Joann P. Palma. "Preclinical Chemosensitization by PARP Inhibitors." In Cancer Drug Discovery and Development, 225–60. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_9.

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Sunada, Shigeaki, and Yoshio Miki. "PARP Inhibitors: Mechanism of Action." In Hereditary Breast and Ovarian Cancer, 281–92. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-4521-1_18.

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Canan, Stacie S. "Structure Based Design of PARP Inhibitors." In Cancer Drug Discovery and Development, 205–21. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_8.

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Conference papers on the topic "PARP1 Inhibitors"

1

Pignochino, Ymera, Federica Capozzi, Lorenzo D’ambrosio, Carmine Dell’aglio, Marco Basiricò, Paola Boccone, Erica Palesandro, et al. "Abstract 3709: PARP1 expression (PARP1expr) drives synergy between PARP1 inhibitors (PARP1-Is) and trabectedin (TR)." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-3709.

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Hopkins, Todd A., Yan Y. Shi, Enrico L. DiGiammarino, Sanjay C. Panchal, Gui-Dong G. Zhu, Thomas D. Penning, Eric F. Johnson, and David Maag. "Abstract 2850: Talazoparib (BMN-673) possesses greater PARP1 trapping activity than structurally distinct PARP inhibitors with identical PARP1 binding properties." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2850.

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Gill, Sonja J., Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, et al. "Abstract 1374: The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1374.

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Lu, Zhen, Wequn Mao, Lan Pang, Janice M. Santiago-O'Farrill, Haling Yang, Ahmed Ahmed, Hariprasad Vankayalapati, and Robert C. Bast. "Abstract 324: SIK2 inhibitors regulate DNA repair pathway and sensitize ovarian cancer to PARP1 inhibitors." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-324.

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Telli, ML. "Abstract ES12-1: Clinical indications of PARP1 inhibitors and other targets." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-es12-1.

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Deng, Ou, Sweta Dash, Thales Nepomuceno, Ming D. Han, Bin Fang, Doug Marchion, Alvaro N. Monteiro, and Uwe Rix. "Abstract B022: PARP1 complex composition as a predictor of response to PARP inhibitors in BRCA-linked ovarian carcinoma." In Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-b022.

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Hopkins, Todd A., Julie L. Wilsbacher, Enrico L. DiGiammarino, Sanjay C. Panchal, Gui-Dong Zhu, Thomas D. Penning, Eric F. Johnson, and David Maag. "Abstract C52: PARP1 trapping activity of PARP inhibitors is associated with cytotoxicity in both cancer cells and healthy bone marrow." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-c52.

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Deng, Ou, Sweta Dash, Thales Nepomuceno, Bin Fang, Douglas Marchion, John Koomen, Alvaro N. Monteiro, and Uwe Rix. "Abstract P018: Integrative proteomics of PARP1 protein complexes and post-translational modifications implicates DDR and AKT-mTOR signaling in mediating response or primary resistance of ovarian carcinoma cells to PARP1 inhibitors." In Abstracts: AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1535-7163.targ-21-p018.

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Gay, Carl M., Pan Tong, Lerong Li, C. Allison Stewart, Triparna Sen, Bonnie S. Glisson, John V. Heymach, Jing Wang, and Lauren Averett Byers. "Abstract 2822: ATR inhibitors are active as single agents and in combination with PARP1 and ATM inhibitors in molecularly distinct subsets of small cell lung cancer models." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-2822.

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Mukhopadhyay, Asima, Nicola Curtin, and Richard Edmondson. "Clinico-pathological correlation of homologous recombination status in epithelial ovarian cancer: Surgeon’s perspective." In 16th Annual International Conference RGCON. Thieme Medical and Scientific Publishers Private Ltd., 2016. http://dx.doi.org/10.1055/s-0039-1685292.

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Background: TCGA data using expensive multi-modality diagnostic platforms have shown that 50% epithelial ovarian cancers (EOCs) are estimated to be homologous recombination (HR) deficient (HRD). We developed a functional assay for HR using gamma H2AX-Rad51 immunofluoresence.[1] Methods: Primary cultures were developed in 50 consecutive EOCs from ascetic fluid and HR assay was performed. Results: 50% patients were HRD based on the functional assay and show improved ex-vivo chemosensitivity to PARP inhibitor (PARPi) (PPV = 92%, NPV = 100%). HRD patients showed improved platinum sensitivity (53.8% vs 16.7%), survival (12 month OS - 41.7% vs. 11.5%) and optimal cytoreduction (80% vs. 62%) rates compared to HR competent (HRC) tumours which are less responsive and represent an unmet clinical need. Conclusions: Personalised surgical and chemotherapeutic strategies may be developed for HR stratified EOCs. Primary surgery may be the preferred approach in HRC due to poor chemoresponse; surgical expertise/environment should be optimised to ensure optimal surgical outcome. Intra-operative hyperthermic treatment and selective HR inhibitors may improve subsequent chemoresponse in HRC and are currently being investigated.
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Reports on the topic "PARP1 Inhibitors"

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Cai, Zhaolun, Chunyu Liu, Chen Chang, Chaoyong Shen, Yuan Yin, Xiaonan Yin, Zhiyuan Jiang, et al. Comparative safety of PARP inhibitors in cancer: A network meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, March 2021. http://dx.doi.org/10.37766/inplasy2021.3.0018.

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Yazinski, Stephanie. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers. Fort Belvoir, VA: Defense Technical Information Center, December 2013. http://dx.doi.org/10.21236/ada612869.

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Yazinski, Stephanie. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers. Fort Belvoir, VA: Defense Technical Information Center, December 2014. http://dx.doi.org/10.21236/ada614186.

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4

Dent, Paul, and Yong Tang. PARP Inhibitors Synergize With Loss of Checkpoint Control to Kill Mammary Carcinoma Cells. Fort Belvoir, VA: Defense Technical Information Center, June 2011. http://dx.doi.org/10.21236/ada555901.

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5

Konstantinopoulos, Panagiotis. A Gene Expression Profile of BRCAness that Predicts for Responsiveness to Platinum and PARP Inhibitors. Fort Belvoir, VA: Defense Technical Information Center, August 2014. http://dx.doi.org/10.21236/ada613331.

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Zhang, Meilin, Jian Song, Hongguang Yang, Feng Jin, and Ang Zheng. Efficacy and safety of PARP inhibitors in breast cancer: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, October 2022. http://dx.doi.org/10.37766/inplasy2022.10.0105.

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Shao, Fengping, Shanyang He, Yanyun Duan, Yunhe Zhao, Yinguang LI, and Lan Jing. A meta-analysis of efficacy of PARP inhibitors versus conventional therapy or placebo in various cancers patients. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, June 2020. http://dx.doi.org/10.37766/inplasy2020.6.0013.

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8

Wu, Meng, HongMei Wang, and ZhengXiang Han. Comparison of PARP Inhibitors as Maintenance Therapy for Platinum-Sensitive Recurrent Ovarian Cancer: A Network Meta-Analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, June 2021. http://dx.doi.org/10.37766/inplasy2021.6.0033.

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Shea, Lonnie D. Identification of a PARP Inhibitor Sensitivity Signature in Breast Cancer Using a Novel Transcription Factor Activity Array. Fort Belvoir, VA: Defense Technical Information Center, March 2012. http://dx.doi.org/10.21236/ada559941.

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DeSoto, Joseph A. The Treatment of BRCA1/2 Hereditary Breast Cancer and Sporadic Breast Cancer with Poly(ADP-ribose) PARP-1 Inhibitors and Chemotherapy. Fort Belvoir, VA: Defense Technical Information Center, September 2008. http://dx.doi.org/10.21236/ada502786.

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