Relevant bibliographies by topics / PARP inhibitory

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  1. Journal articles
  2. Dissertations / Theses
  3. Books
  4. Book chapters
  5. Conference papers
  6. Reports

Academic literature on the topic 'PARP inhibitory'

Author: Grafiati
Published: 4 June 2021
Last updated: 14 February 2022

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Journal articles on the topic "PARP inhibitory"

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Li, Wenchao, Bowen Pan, Yang Shi, Meiying Wang, Tianjiao Han, Qing Wang, Guifang Duan, and Hongzheng Fu. "Identification of poly(ADP-ribose)polymerase 1 and 2 (PARP1/2) as targets of andrographolide using an integrated chemical biology approach." Chemical Communications 57, no. 51 (2021): 6308–11. http://dx.doi.org/10.1039/d1cc02272e.

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Andrographolide is the first PARP natural product inhibitor that does not contain an amide structure and has an inhibitory activity in the nanomolar range. This chemical structure is significant for expanding the structural type of PARP inhibitors.
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Li, Jiaguo, Dian Xiao, Lianqi Liu, Fei Xie, Wei Li, Wei Sun, Xiaohong Yang, and Xinbo Zhou. "Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib." Molecules 25, no. 2 (January 18, 2020): 407. http://dx.doi.org/10.3390/molecules25020407.

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In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.
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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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Gurkan-Alp, A. Selen, Mehmet Alp, Arzu Z. Karabay, Asli Koc, and Erdem Buyukbingol. "Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 Breast Cancer Cell Viability." Anti-Cancer Agents in Medicinal Chemistry 20, no. 14 (October 14, 2020): 1728–38. http://dx.doi.org/10.2174/1871520620666200502001953.

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Background: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways. Objective: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer activities. Methods: Compounds were tested by cell-free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer, and L929 fibroblast cell lines. Results: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells, whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity. Conclusion: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells, and further research will enlighten the underlying mechanisms of their effects.
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Toledano, Elie, Vasily Ogryzko, Antoine Danchin, Daniel Ladant, and Undine Mechold. "3′-5′ Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo." Biochemical Journal 443, no. 2 (March 27, 2012): 485–90. http://dx.doi.org/10.1042/bj20111057.

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pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity.
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Cheong, Woo-Chang, Joo-Hee Park, Hye-Ri Kang, and Moon Jung Song. "Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus." Journal of Virology 89, no. 18 (July 8, 2015): 9676–82. http://dx.doi.org/10.1128/jvi.00559-15.

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ABSTRACTIn Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADP-ribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus.IMPORTANCEGammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication.
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Xin, Minhang, Jiajia Sun, Wei Huang, Feng Tang, Zhaoyu Liu, Qiu Jin, and Jia Wang. "Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors." Future Medicinal Chemistry 12, no. 19 (October 2020): 1691–707. http://dx.doi.org/10.4155/fmc-2020-0009.

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Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate.
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Zhou, Yunjiang, Shi Tang, Tingting Chen, and Miao-Miao Niu. "Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors." Molecules 24, no. 23 (November 22, 2019): 4258. http://dx.doi.org/10.3390/molecules24234258.

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Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1–4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.
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Malka, Matthews M., Julia Eberle, Kathrin Niedermayer, Darius P. Zlotos, and Lisa Wiesmüller. "Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells." Biomolecules 11, no. 7 (July 3, 2021): 981. http://dx.doi.org/10.3390/biom11070981.

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The genetic principle of synthetic lethality has most successfully been exploited in therapies engaging Poly-ADP-ribose-polymerase (PARP) inhibitors to treat patients with homologous recombination (HR)-defective tumors. In this work, we went a step further following the idea of a local molecular cooperation and designed hybrid compounds M1–M3. The drug conjugates M1–M3 combine Olaparib, the first PARP inhibitor approved for clinical use, with Cpd 1, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in M2 and M3, the parental drugs are linked by -CO-(CH2)n-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of Olaparib in M1. Monitoring anti-survival effects of M1–M3 in six breast cancer cell lines of different molecular subtypes showed that in each cell line, at least one of the drug conjugates decreased viability by one to two orders of magnitude compared with parental drugs. While triple-negative breast cancer (TNBC) cells with frequent BRCA1 pathway dysfunction were sensitive to spacer-linked hybrid compounds M1 and M2 regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate M1 only, suggesting different spatial requirements for dual inhibition in these two groups of cell lines. These results demonstrate that, depending on chemical linkage, dual PARP1-RAD51 inhibitory drugs can either sensitize non-TNBC and re-sensitize TNBC cells, or discriminate between these groups of cells.
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Keung, Man Yee, Yanyuan Wu, Francesca Badar, and Jaydutt V. Vadgama. "Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status." Journal of Clinical Medicine 9, no. 4 (March 30, 2020): 940. http://dx.doi.org/10.3390/jcm9040940.

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Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven to be beneficial to patients with metastatic breast cancer with BRCA1/2 (BReast CAncer type 1 and type 2 genes) mutations. However, certain PARPi in pre-clinical studies have been shown to inhibit cell growth and promote the death of breast cancer cells lacking mutations in BRCA1/2. Here, we examined the inhibitory potency of 13 different PARPi in 12 breast cancer cell lines with and without BRCA-mutations using cell viability assays. The results showed that 5 of the 8 triple-negative breast cancer (TNBC) cell lines were susceptible to PARPi regardless of the BRCA-status. The estrogen receptor (ER) negative/ human epidermal growth factor receptor 2 (HER2) positive (ER-/HER2+) cells, SKBR3 and JIMT1, showed high sensitivity to Talazoparib. Especially JIMT1, which is known to be resistant to trastuzumab, was responsive to Talazoparib at 0.002 µM. Niraparib, Olaparib, and Rucaparib also demonstrated effective inhibitory potency in both advanced TNBC and ER-/HER2+ cells with and without BRCA-mutations. In contrast, a BRCA-mutant TNBC line, HCC1937, was less sensitive to Talazoparib, Niraparib, Rucaparib, and not responsive to Olaparib. Other PARPi such as UPF1069, NU1025, AZD2461, and PJ34HCl also showed potent inhibitory activity in specific breast cancer cells. Our data suggest that the benefit of PARPi therapy in breast cancer is beyond the BRCA-mutations, and equally effective on metastatic TNBC and ER-/HER2+ breast cancers.
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Dissertations / Theses on the topic "PARP inhibitory"

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Block, Katherine M. "Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcription." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/194826.

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Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.
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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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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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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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Smar, Michael William. "Part 1: Reversible and irreversible inhibitors of aldose reductase as probes of the inhibitor binding site. Part 2: Synthesis of permanently charged and permanently uncharged dopamine agonists /." The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487597424138323.

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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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Davies, Glyn Daniel. "Inhibitor studies on para-aminobenzoic acid synthase." Thesis, University of Cambridge, 2003. https://www.repository.cam.ac.uk/handle/1810/265461.

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Para-aminobenzoic acid (PABA) synthase is a three-subunit enzyme system that catalyses the conversion of chorismic acid top-aminobenzoic acid in plants and microorganisms. P ABA is then incorporated into folic acid an essential nutrient for mammals and utilised in the transfer of one-carbon units. For this reason it is a potential target for herbicidal and antibiotic development. A glutamine amidotransferase and ADC synthase form a heterodimeric complex and carry out the amino substitution reaction to yield 4-amino-4-deoxychorismate (ADC). A separate subunit, ADC lyase, then carries out the elimination of pyruvate to yield P ABA. My research describes a number of advances in the purification and assay system used and the organic synthesis of inhibitors of ADC synthase. The purification and characterisation was carried out of newly cloned 6-His tagged PABA synthase enzymes from E. coli. engineered to overexpress these proteins. The assay system used was refined and substrate kinetic data obtained. Results were compared to 'wild-type' enzyme and data obtained when the assay system has ammonium in place of glutamine and glutamine amidotransferase. The crystal structures of 'wild-type' ADC synthase and ADC Lyase enzymes are only recently available in the literature. Inhibition data for compounds synthesised was obtained initially via a fluorescence screen and then to greater accuracy via a continuous UV assay. My inhibitor studies revealed a close structural analogue of 4-amino-4- deoxychorismate, 4-amino-3-[1-carboxyethoxy] benzoate as the best inhibitor (ea. 20 ?M) of P ABA synthase so far. The synthesis of a number of aromatic compounds to act as m1m1cs of ADC was accomplished. An aromatic nitro group was reduced to give an amine using tin(II) chloride and hydrogenation reactions. Other forms of nitrogen protection using carbamates and bissilyl protection were also utilised. The formation of an enol pyruvyl group was accomplished in an original manner using lithium diisopropylamine to deprotonate a proton alpha to an ester. This was followed by selenation and elimination/oxidation to form the required methylene group as an a,,B-unsaturated ester. Alternative methods, involving a rhodium catalysed hydroxy insertion followed by either a Wadsworth-Horner-Emmons modified Wittig reaction with formaldehyde or alkylation with Eschermosers' Salt, were also carried out. Further synthesis of ADC and chorismate analogues was performed using the aza-Cope and oxy-Cope rearrangements of oxygen-alkylated hydroxybenzoates and N-alkylated aromatic amines. The organic synthesis of an inhibitor containing vinyl fluoride functionality has been the focus of previous studies. The biosynthesis of 6-fluorochorismate led to the discovery that this species was an irreversible inhibitor of the P ABA synthase system. Synthesis of a vinyl fluoride was achieved via a vinyl triflate and vinyl trialkylstannane utilising a lithium cuprate reagent. Fluorination was carried out using XeF2 in the presence of a catalytic amount of Ag(OTf). The mild conditions achieved form a foundation for the synthesis of more complex 6-fluorochorismate analogues. Further synthesis was carried out to try to synthesise a Michael acceptor for an enzyme active-site nucleophile based on a proposed mechanism for the irreversible inhibitor. Dianion alkylation chemistry using �sodium hydride followed by n-BuLi was used to control regioselectivity in the alkylation of a cyclic ,8-ketoester. In a one-pot synthesis, selenyl elimination/oxidation of the alkylated cyclic ,8-ketoester was used to form an extended delocalised system with the potential to act as a Michael acceptor.
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Verástegui, Pereira Karina Meliza. "Utilidad del Cociente Inhibitorio en la interpretación del antibiograma para Enterobacterias aisladas de Urocultivos en pacientes ambulatorios, Hospital Nacional Docente Madre Niño (HONADOMANI) “San Bartolomé” Febrero - Diciembre 2014 Lima-Perú." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2015. https://hdl.handle.net/20.500.12672/4391.

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Introducción: La interpretación del antibiograma por la CLSI tiende a brindarnos cierta información para elegir mejor el antimicrobiano capaz de inhibir o disminuir el crecimiento bacteriano, sin embargo existe una falta de concordancia de la prueba de susceptibilidad in vitro de un patógeno aislado del tracto urinario con la respuesta de la eficacia clínica o selección del antibacteriano. Objetivo: Determinar la utilidad del cociente inhibitorio en la interpretación del Antibiograma realizadas para enterobacterias aisladas de urocultivos positivos de pacientes ambulatorios. (...) Resultados: Fueron analizados 223 urocultivos positivos a enterobacterias en pacientes ambulatorios. El principal uropatógenos aislado fue Escherichia coli (86.5%). Se obtuvo una interpretación de respuesta terapéutica favorable por el cociente inhibitorio en todos los casos de cepas categorizadas como sensible a Fluoroquinolonas, Betalactámico y aminoglucósidos. La cepas que fueron categorizadas como intermedio, se obtuvo en todas ellas una interpretación de respuesta terapéutica favorable por cociente inhibitorio con una frecuencia para cada antibiótico probado de: Ampicilina (5), Ceftriaxone (3), Gentamicina (4); y Ciprofloxacino (5); a excepción de la Amikacina que presentó un caso de cepa intermedio con una interpretación de respuesta terapéutica no favorable por CI. Por otro lado, se mostró que la cepas como intermedios para cefalotina por la interpretación convencional se obtuvo una interpretación de una respuesta terapéutica favorable con el CI en el 100%(52) de los hallados con un IC95% (-6.9% a 6.9%). Para los casos de cepas categorizadas como “resistente”, se observó un porcentaje de ellas interpretadas con una respuesta terapéutica favorable por el CI de 29.5% (13/44) para ceftriaxone, de 27.5% (11/40) para Gentamicina, 12.4% (11/89) para ciprofloxacino, y 8.1% (6/74) para cefalotina. Se comparó la interpretación de sensibilidad para cepas de E.coli y cepas con presencia de BLEE, entre las dos interpretaciones. Para el primer caso, solo se observó para cefalotina con 58(30%) de cepas más sensible, interpretadas como respuesta terapéutica favorable significativo con un IC 95% (20.3% a 39.0%) dadas por el cociente inhibitorio. Para el segundo caso, de cepas E.coli productoras de BLEE mostró una diferencia significativa, a favor cepas interpretadas con respuesta terapéutica favorable por el CI para Ceftriaxone con 9(26.5%) con un IC95% (10.1% a 42.8%). Conclusiones: El uso del cociente inhibitorio en la interpretación del antibiograma nos podría dar mayores alternativas en la elección terapéutica siempre que dichos resultados sean valorados a través de un seguimiento del paciente por el médico, siendo así se disminuiría con ello los casos de resistencia, el uso de antibióticos de amplio espectro, que además pueden ser costosos, y poder modificar la dosis, etc.
--- Introduction: The interpretation by the CLSI antimicrobial susceptibility tends to provide certain information to better choose the antimicrobial capable of inhibiting or reducing bacterial growth, but there is a mismatch of in vitro susceptibility testing of isolated urinary tract pathogen the response of the clinical efficacy of antibacterial or selection. Objective: To determine the usefulness of the inhibitory quotient in the interpretation of Antibiogram made for enterobacteria isolated from urine cultures from outpatients. (...) Results: There were 223 positive enterobacteriaceae in outpatient urine cultures. The main uropathogens isolated was Escherichia coli (86.5%). An interpretation of favorable therapeutic response by the inhibitory quotient in all cases categorized as sensitive strains Fluoroquinolones, Betalactam and aminoglycoside was obtained. The strains were categorized as intermediate, an interpretation favorable therapeutic response was obtained for all inhibitory quotient with a frequency for each antibiotic tested: Ampicillin (5), Ceftriaxone (3), gentamicin (4); and Ciprofloxacin (5); Amikacin except that presented a case intermediate strain with an interpretation of therapeutic response CI unfavorable. Furthermore, it was shown that the strains as intermediates for the conventional interpretation cephalothin an interpretation of a positive therapeutic response with CI in 100% (52) of those found with a 95% CI (-6.9% to 6.9% was obtained). For cases of strains categorized as resistan, a percentage of them performed with a favorable therapeutic response by the CI 29.5% (13/44) for ceftriaxone, 27.5% (11/40) for gentamicin, 12.4% was observed (11/89) to ciprofloxacin and 8.1% (6/74) to cephalothin. The interpretation of sensitivity for E. coli strains and strains with BLEE presence between the two interpretations were compared. In the first case, only it observed for cephalothin 58 (30%) of more sensitive strains interpreted as significant favorable therapeutic response with 95% (20.3% to 39.0%) given by the inhibitory quotient. For the second case of E.coli BLEE producing strains it showed a significant difference in favor strains with favorable therapeutic response interpreted by the CI to Ceftriaxone 9 (26.5%) with a 95% (10.1% to 42.8%). Conclusions: The use of inhibitory quotient in the interpretation of susceptibility could give us more alternatives in the therapeutic choice provided that such results are assessed through monitoring of the patient by the physician, and still be diminished thereby cases of resistance, use of broad-spectrum antibiotics, which can also be expensive, and modify the dose, etc. Keywords: inhibitory ratio, maximum concentration of antimicrobial susceptibility, minimum inhibitory concentration, pharmacodynamics, pharmacokinetics.
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Ordway, Gregory A., Attila Szebeni, Liza J. Hernandez, Jessica D. Crawford, Katalin Szebeni, Michelle J. Chandley, Katherine C. Burgess, Corwin Miller, Erol Bakkalbasi, and Russell W. Brown. "Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2768.

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Many patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors.
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Fraser, Rebecca Dawn. "Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction : Part II structure-activity relationship for a series of glycosidase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/30508.

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Books on the topic "PARP inhibitory"

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

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Adrenergic Activators and Inhibitors: Part II. Springer, 2011.

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PARP as a Therapeutic Target (Handbooks in Pharmacology and Toxicology). CRC, 2002.

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Inhibitors of the Ras Superfamily G-Proteins, Part B. Elsevier Science & Technology, 2013.

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Tamanoi, Fuyuhiko. Inhibitors of the Ras Superfamily G-Proteins, Part A. Elsevier Science & Technology Books, 2013.

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Shokat, Kevan M. Protein Kinase Inhibitors in Research and Medicine, Part B. Elsevier Science & Technology Books, 2013.

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Inhibitors of the Ras Superfamily G-proteins, Part A. Elsevier, 2013. http://dx.doi.org/10.1016/c2012-0-03660-5.

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Inhibitors of the Ras superfamily G-proteins, Part B. Elsevier, 2013. http://dx.doi.org/10.1016/c2012-0-03661-7.

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Book chapters on the topic "PARP inhibitory"

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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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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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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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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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Clift, Ashley K., Nicholas Coupe, and Mark R. Middleton. "Clinical Trials of PARP Inhibitors with Chemotherapy." In Cancer Drug Discovery and Development, 511–31. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_22.

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Carruthers, Ross, and Anthony J. Chalmers. "Combination of PARP Inhibitors with Clinical Radiotherapy." In Cancer Drug Discovery and Development, 533–51. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_23.

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Ferraris, Dana. "Overview of PARP Inhibitor Design and Optimization." In Cancer Drug Discovery and Development, 183–203. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14151-0_7.

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Conference papers on the topic "PARP inhibitory"

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Im, Seock-Ah, Ahrum Min, Hyung-Seok Hur, Young-Kwang Yoon, Sang Hyun Song, Lucy Riches, Charlotte Knights, et al. "Abstract 1775: Growth inhibitory effect of PARP inhibitor olaparib in gastric cancer cells." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1775.

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Montagnoli, Alessia, Sonia Rainoldi, Stefania Mazzoleni, Antonella Ciavolella, Rosita Lupi, Elena Casale, Marina Ciomei, et al. "Abstract 3259: Novel isoquinolinone derivatives with dual PARP-1/PARP-3 inhibitory activity are highly active against pTEN mutated colorectal cancer and glioblastoma models.." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3259.

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Maclay, Tyler, Melinda Day, and Kevin Mills. "Abstract 363: CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-363.

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Fehling, Samuel C., Aubrey L. Miller, James E. Bradner, and Karina J. Yoon. "Abstract 5824: The BET inhibitor JQ1 sensitizes cholangiocarcinoma cells to PARP 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.am2018-5824.

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Maclay, Tyler, Melinda Day, and Kevin Mills. "Abstract 363: CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-363.

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Dey, Nandini, Jennifer H. Carlson, Pradip De, and Brian Leyland-Jones. "Abstract B12: Co-targeting PTEN-defined TNBC with p110beta-isoform specific inhibitor and PARP inhibitor BMN 673: A predictive context to sensitize PARP inhibitors in TNBC." In Abstracts: AACR Special Conference: Advances in Breast Cancer; October 17-20, 2015; Bellevue, WA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.advbc15-b12.

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Ellis, V. E., M. F. Scully, and V. V. Kakkar. "KINETICS OF HEPARIN CO-FACTOR II (HCII):THROMBIN AND ANTITHROMBIN III (ATIII):THROMBIN INTERACTION. MOLECULAR WEIGHT DEPENDENCY." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644350.

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The influence of increasing concentrations of heparin of different molecular mass (Mr) has been compared in potentiation of the rate of HCII:thrombin interaction and of ATIII:thrombin interaction under pseudo first order conditions. Unfractionated and fractionated heparin showed a concentration dependent ascending and descending limb of stimulation of the rate which was closely similar for both inhibitors. Unfractionated heparin and fractions of 16.5 KDa or less showed a peak acceleration of the rate of interaction of thrombin with both inhibitors at 0.3×10−6 heparin although the observed maximum rate at this peak decreased with fall in Mr. For both inhibitors two high Mr fractions (22KDa and 32KDa) showed peak stimulation at a lower heparin concentration (0.3×10−7M) and 1.5 to 2 fold greater increase in rate than that observed with unfractionated heparin. Under these conditions it could be calculated that the potency of a 32KDa fraction was 1200iu/mg with respect to UF heparin (150iu/mg). Three further pools were prepared and ATIII .high affinity fraction prepared by chromatography. Acceleration of rate of interaction was measured according to concentration and inverse plots gave values for apparent Kd amd maximal rate.These results suggest that differences in the profiles of stimulation by high Mr fractions to those of lower Mr are related to higher binding affinities for the inhibitor permitting maximal binding of heparin before the descending part of the slope due to saturation of thrombin (according to the template hypothesis). Although close similarity was found between heparin stimulation of HCII and ATIII, potentiation of HCII inhibitory activity differed in that it was reversed by lower ionic strength and was not reversed by a heparin pentasaccharide with high affinity for ATIII.
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Makvandi, Mehran, Brian P. Lieberman, Kuiying Xu, Redmond-Craig Anderson, Chenbo Zeng, David A. Mankoff, Daniel A. Pryma, Roger A. Greenberg, and Robert H. Mach. "Abstract C15: Predicting response to PARP inhibitors through quantitative measurements of PARP activity in live BRCA1 mutated cells with a radio-iodinated PARP inhibitor." 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-c15.

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Heath, Steve, Olav Martin Selle, Elisbeth Storås, Bjørn Juliussen, Alan Thompson, Clare Johnston, Kim Vikshåland, Linn-Øydis Lid, Thomas Gundersen, and Thomas Bjellaas. "Squeezing Sub-Sea Wells Co-Mingled in the Same Flowline on the Norne Field." In SPE International Oilfield Scale Conference and Exhibition. SPE, 2014. http://dx.doi.org/10.2118/spe-169793-ms.

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Abstract An essential part of any scale squeeze management strategy for any oilfield is the capability to accurately and precisely determine the residual scale inhibitor concentration in the produced fluids. These data in combination with ion analysis and well productivity index are essential to determine the lifetime efficiency of scale squeeze treatments. For sub-sea wells comingled in the same flowline this presents a significant challenge due to mixed brine composition in the flowline and the requirements to analyse multiple families of scale squeeze inhibitors in the same sample without interference from the continuously injected wellhead/topside scale inhibitors and any other production chemicals that maybe applied. In recent years the use of environmentally acceptable polymeric scale squeeze inhibitors has increased. The accurate and precise analysis of polymers has proved to be difficult and a toolbox of advanced scale inhibitor analysis techniques has therefore been developed to improve scale management capability in sub-sea fields.1 This technology is based upon a range of novel analysis techniques, including Liquid Chromatography-Mass Spectroscopy (LC-MS), which have demonstrated the feasibility to detect multiple families of scale inhibitors at low levels with improved confidence along with the potential for squeezing wells co-mingled at the same flowline with different scale inhibitors. This was not considered possible before and recent refinements have been targeted towards the specific challenges on the Norne field, where it was required to detect three different polymeric scale squeeze inhibitors in the same flow line sample in the presence of the continuously applied wellhead and topside polymeric scale inhibitor. This paper presents brief details of the progress made with new analysis techniques and highlights the application benefits of the implementation of these novel scale inhibitor analysis techniques in the Norne field. Data will be presented from a proof of concept study for squeezing three sub-sea wells co-mingled in the same flowline with three different polymeric scale squeeze inhibitors, namely, a phosphorus containing polyamine, a phosphorus tagged quaternary amine terpolymer and a phosphorus tagged sulphonated copolymer all in the presence of the wellhead/topside sulphonate/carboxylate copolymer. The implications of different detection limits for the three different polymers on the individual well treatment lifetimes and re-squeeze frequency will also be discussed.
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Uddin, Md Hafiz, Yiwei Li, Amro Aboukameel, Husain Y. Khan, Vijendra Singh, Shriya Reddy, Suresh Kumar Balasubramanian, et al. "Abstract 1091: Nuclear export inhibitor KPT-8602 synergize with PARP inhibitors in castration resistant metastatic prostate cancer." 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.am2021-1091.

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Reports on the topic "PARP inhibitory"

1

Lance, Richard, and Xin Guan. Variation in inhibitor effects on qPCR assays and implications for eDNA surveys. Engineer Research and Development Center (U.S.), August 2021. http://dx.doi.org/10.21079/11681/41740.

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Aquatic environmental DNA (eDNA) surveys are sometimes impacted by polymerase chain reaction (PCR) inhibitors. We tested varying concentrations of different inhibitors (humic, phytic, and tannic acids; crude leaf extracts) for impacts on quantitative PCR (qPCR) assays designed for eDNA surveys of bighead and silver carp (Hypophthalmichthys nobilis and Hypophthalmichthys molitrix). We also tested for inhibition by high concentrations of exogenous DNA, hypothesizing that DNA from increasingly closely related species would be increasingly inhibitory. All tested inhibitors impacted qPCR, though only at very high concentrations — likely a function, in part, of having used an inhibitor-resistant qPCR solution. Closer phylogenetic relatedness resulted in inhibition at lower exogenous DNA concentrations, but not at relatively close phylogenetic scales. Inhibition was also influenced by the qPCR reporter dye used. Importantly, different qPCR assays responded differently to the same inhibitor concentrations. Implications of these results are that the inclusion of more than one assay for the same target taxa in an eDNA survey may be an important countermeasure against false negatives and that internal positive controls may not, in the absence of efforts to maximize inhibition compatibility, provide useful information about the inhibition of an eDNA assay.
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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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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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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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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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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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