Bifunctional Inhibitor

Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

... to PARP inhibitors as cancer chemosensitisers [3]. AG14361 (one of a series of tricyclic benzimidazole carboxamide PARP inhibitors [4] is a potent chemo- and radiosensitizer in vitro and in vivo [5] and inhibits the repair of double strand breaks in DNA, sensitizing cancer cells to ionising radiation [6]. Further development of this series of inhibitors ... was to determine the potency of rucaparib relative to that of ML-9, a commercially available MLCK inhibitor. Although neither inhibitor evoked maximal inhibition of MLCK in the concentration range tested (10 nM—100 μM), rucaparib was ten times more potent an inhibitor of MLCK activity than ML-9 (IC50s of 55 μM [11] and 560 μM respectively; Fig. 1D). Determination ... 16 Vasoactivity of PARP Inhibitor Rucaparib If vasodilation is a common feature of PARP inhibitors containing the nicotinamide pharmacophore, it would broaden the range of chemotherapeutics beyond temozolomide and the topoisomerase I poisons that could be enhanced. Indeed, there are numerous clinical trials combining PARP inhibitors with paclitaxel,
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The kinase inhibitor SFV785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly.

... cells. Results Synthesis and characterization of SFV785, a kinase inhibitor that inhibits HCV replication SRPK inhibitor, SRPIN340, has been reported to have antiviral activity against several RNA viruses including HIV, Sindbis virus, and HCV [9,18]. In an attempt to optimize the anti-HCV reactivity of this inhibitor, we synthesized ten new (iso)nicotinoyl derivatives ... approximately 3.6 billion PLoS ONE | 1 August 2011 | Volume 6 | Issue 8 | e23246 Kinase Inhibitor to Dengue Virus Assembly available from the Millipore website ( output/pdf/ProfilingProfilingBook_en.pdf). The inhibitory effect on the other kinases was examined with the Millipore Kinase ProfilerTM Service using ... possibly more efficiently than the replication of the HCV Rep-Feo subreplicon. The parent compound of SFV785, SRPIN340, is an inhibitor of the SR protein kinases SRPK1 and SRKP2 [18]. In order to determine if SFV785 retained its kinase inhibitory activity and specificity for SRPK, we screened the effect of this compound on the kinase activity of a library
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Biochemical characterization of CTX-M-15 from Enterobacter cloacae and designing a novel non-β-lactam-β-lactamase inhibitor.

... conventional b-lactam antibiotic -inhibitor combinations, we aspire to design a non-b-lactam core containing b-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-b-lactam based inhibitor (ZINC03787097). The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. ... bacterial resistance against such inhibitors has been reported owing to the ability of bacteria to hydrolyse the b-lactam core of these inhibitors [17–19]. Porin channel mutation and overexpression of b-lactamases in the presence of b-lactam based inhibitor are other mechanisms that confer increasing resistance against such inhibitors [20]. Thus, there is ... enteric bacilli [13–15]. Several b-lactamase inhibitors that are commonly used in combination with b-lactam antibiotics are clavulanic acid, tazobactam and sulbactam. Among class A enzymes, tazobactam is the most potent inhibitor followed by clavulanic acid and sulbactam [16]. The core structure of these inhibitors contains a blactam ring (Figure 1).
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Liver safety of two nucleoside analogs plus efavirenz, nevirapine or a ritonavir-boosted protease inhibitor in HIV/HCV-coinfected drug-naïve patients

... Papers Treatment Strategies Chairs: O211 08.30–08.50 The state of PI monotherapy and NRTI-sparing therapy Jose Arribas (Spain) O212 08.50–09.05 Ritonavir-boosted protease inhibitor monotherapy is 6% less effective than combination antiretroviral therapy in a metaanalysis Wouter Bierman (The Netherlands) O213 09.05–09.20 Low-level viraemia during ... therapy in antiretroviralnaïve adults: rapid and potent 24-week antiviral responses in SPRING-1 (ING112276) Jürgen Rockstroh (Germany) O435 12.00–12.15 Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961) Sherene Min (USA) 12.15–12.30 Panel discussion 12.30–12.40 Closing
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Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation.

... LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in ... Annexin A2 Is a Natural Extrahepatic Inhibitor of the PCSK9-Induced LDL Receptor Degradation Nabil G. Seidah2, Steve Poirier2, Maxime Denis2, Rex Parker4, Bowman Miao4, Claudio Mapelli4, Annik Prat2, Hanny Wassef3, ... extending our results on the physiological role of AnxA2 in humans. Citation: Seidah NG, Poirier S, Denis M, Parker R, Miao B, et al. (2012) Annexin A2 Is a Natural Extrahepatic Inhibitor of the PCSK9-Induced LDL Receptor Degradation. PLoS ONE 7(7): e41865. doi:10.1371/journal.pone.0041865 Editor: Alberico Catapano, University of Milan, Italy Received
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Lonafarnib is a potential inhibitor for neovascularization.

... atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to ... neovascularization in atherosclerosis, in this study, we sought to investigate the potential effect of lonafarnib, a nonpeptide tricyclic farnesyl transferase inhibitor, on neovascularization. We found that lonafarnib elicits inhibitory effect on neovascularization via disturbing centrosome reorientation and impairing endothelial cell motility. Mechanistically, we showed ... results, we treat HUVECs with tipifarnib, another specific farnesyl transferase inhibitor, which remarkably decreased HDJ-2 farnesylation (Fig 2C). Similarly, we found that tipifarnib (10 μM) was able to suppress wound closure significantly (Fig 2D and 2E), confirming the inhibitory effect of this group of agents on cell motility. Lonafarnib has little
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Interaction of protein C inhibitor with the type II transmembrane serine protease enteropeptidase.

... of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa. Am J Physiol 267: C466–472. 9. Hermans JM, Jones R, Stone SR (1994) Rapid inhibition of the sperm protease acrosin by protein C inhibitor. Biochemistry 33: 5440–5444. 10. Cooper ST, Church FC (1995) Reactive site mutants of recombinant protein C inhibitor. Biochim Biophys ... invasiveness [41,42]. Regulation of EP by protease inhibitors may therefore be not only important in the digestive system, but also in epidermal differentiation and tumor invasion. We analyzed the interaction of EP with serpin-type protease inhibitors (PCI, a1-antitrypsin (A1AT) and AT) and can show that PCI is a strong inhibitor of EP with an apparent 2nd order ... Wang Y, Zeng Y, et al. (2007) Immunolocalization of protein C inhibitor in differentiation of human epidermal keratinocytes. Acta Histochem 109: 461–467. 24. Laurell M, Christensson A, Abrahamsson PA, Stenflo J, Lilja H (1992) Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive
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Plasma autoantibodies against heat shock protein 70, enolase 1 and ribonuclease/angiogenin inhibitor 1 as potential biomarkers for cholangiocarcinoma.

... Lee MH, Tan P (2014) RNH1 regulation of reactive oxygen species contributes to histone deacetylase inhibitor resistance in gastric cancer cells. Oncogene 33: 1527–1537. 53. Chen J, Ou-Yang X, Gao J, Zhu J, He X, et al. (2011) Knockdown of ribonuclease inhibitor expression with siRNA in non-invasive bladder cancer cell line BIU-87 promotes growth and ... all cell lines-derived proteins were observed on stained gels and studied by LC-MS/MS. Among these, heat shock protein 70 (HSP70), enolase 1 (ENO1) and ribonuclease/angiogenin inhibitor 1 (RNH1) obtained the highest matching scores and were thus selected for further validation. Western blot revealed immunoreactivity against HSP70 and RNH1 in the majority ... for CCA. Citation: Rucksaken R, Pairojkul C, Pinlaor P, Khuntikeo N, Roytrakul S, et al. (2014) Plasma Autoantibodies against Heat Shock Protein 70, Enolase 1 and Ribonuclease/Angiogenin Inhibitor 1 as Potential Biomarkers for Cholangiocarcinoma. PLoS ONE 9(7): e103259. doi:10.1371/journal.pone.0103259 Editor: Gabriele Multhoff, Technische Universitaet Muenchen,
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A metal-based inhibitor of NEDD8-activating enzyme.

... ATP-competitive inhibitor of NAE by occupying the ATP-binding domain. Other possible binding poses of 1 and their corresponding docking scores are also included in the Supporting Information (Table S1). Conclusion In summary, we have identified the rhodium(III) complex 1 as a new inhibitor of NAE. The identification of the metal-based inhibitor 1 represents, ... improved selectivity profile [43]. The NAE inhibitor MLN4924 [43] (Figure 1) was recently reported to be effective against both solid (colon, lung) and hematological (myeloma, lymphoma) human cancer cells. We have previously employed high-throughput virtual screening to identify 6,699-biapigenin as only the second inhibitor of NEDD8-activating enzyme from ... structurally complex metal-based enzyme inhibitors that offer comparable potency to organic small molecules [17]. The NEDD8 pathway has recently emerged as a new target for the treatment of cancer [26–33]. Modification of the cullin-RING PLOS ONE | 1 November 2012 | Volume 7 | Issue 11 | e49574 A Metal-Based Inhibitor of NEDD8-Activating Enzyme treating
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Interleukin-27 is a potent inhibitor of cis HIV-1 replication in monocyte-derived dendritic cells via a type I interferon-independent pathway.

... addition IL-27 has been found to have broad anti-viral effects. Recently, IL-27 has been shown to be a potent inhibitor of HIV-1 infection in CD4+ T cells and macrophages. The main objective of this study was to see whether IL-27 has a similar inhibitory effect on HIV-1 replication in dendritic cells (DCs). Monocytes were differentiated into immature ... e59194 IL-27 Inhibits HIV-1 Infection in Dendritic Cells adding 100 mL of radio-immunoprecipitation assay (RIPA) buffer containing a phosphatase inhibitor cocktail (Thermo Fisher Scientific, Waltham, MA) and protease inhibitor cocktail (SigmaAldrich, St. Louis, MO). Protein quantity was estimated using the BCA protein assay reagent (Thermo Fisher Scientific). ... inhibition. This study is the first report showing that IL-27 has significant inhibitory effects on cis HIV-1 replication in DCs. It adds to other studies that demonstrate IL-27 can inhibit HIV-1 replication in CD4+ T cells [8] and macrophages [8,9,10]. In those studies, IL27 appears to have a stronger inhibitory action in macrophages compared to CD4+ T cells and this
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In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes.

... nuclear import inhibitory peptide. Thus, chronic activation of isletinfiltrating T and B cells in autoimmune diabetes may favor the AICD-enhancing effect of the nuclear import inhibitor. This hitherto unreported action of cSN50 in a relevant preclinical T1D model adds autoimmune inflammation to the list of conditions in which a nuclear import inhibitor has ... cell-penetrating nuclear import inhibitor. We found that short-term intracellular delivery of this PLoS ONE | Results Primary lymphocytes and macrophages from NOD mice are susceptible to attenuation of T cell receptor (TCR)and Toll-like receptor (TLR)-evoked pro-inflammatory signaling by a nuclear import inhibitor NOD mice, a widely used ... and IL-1b in BMDM obtained from NOD mice was suppressed. Thus, a nuclear import inhibitor attenuates production of islet-toxic, pro-apoptotic mediators evoked by TCR and TLR agonists in primary immune cells derived from NOD mice. Intracellular delivery of a nuclear import inhibitor to the pancreas reduces islet inflammation (insulitis) The highly effective
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HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice.

... Miyata N, Laniado-Schwartzman M (2005) Cytochrome P450 4A isoform inhibitory profile of N-hydroxy-N9-(4-butyl-2-methylphenyl)-formamidine (HET0016), a selective inhibitor of 20HETE synthesis. Biol Pharm Bull 28: 1651–1654. 7. Chen P, Guo M, Wygle D, Edwards PA, Falck JR, et al. (2005) Inhibitors of cytochrome P450 4A suppress angiogenic responses. Am ... 10595, United States of America * OPEN ACCESS Citation: Borin TF, Zuccari DAPC, Jardim-Perassi BV, Ferreira LC, Iskander ASM, et al. (2014) HET0016, a Selective Inhibitor of 20-HETE Synthesis, Decreases Pro-Angiogenic Factors and Inhibits Growth of Triple Negative Breast Cancer in Mice. PLoS ONE 9(12): e116247. doi:10.1371/ journal.pone.0116247 Editor: ... collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abstract A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors.
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Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model.

... Sensitivity of MRI Tumor Biomarkers to VEGFR Inhibitor Therapy in an Orthotopic Mouse Glioma Model Christian T. Farrar1*., Walid S. Kamoun2., Carsten D. Ley2., Young R. Kim1, Ciprian Catana1, Seon J. Kwon1, Bruce R. Rosen1, ... complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI) and a slight decrease in the water apparent ... interpret the therapy-induced changes in the tumor physiology. Citation: Farrar CT, Kamoun WS, Ley CD, Kim YR, Catana C, et al. (2011) Sensitivity of MRI Tumor Biomarkers to VEGFR Inhibitor Therapy in an Orthotopic Mouse Glioma Model. PLoS ONE 6(3): e17228. doi:10.1371/journal.pone.0017228 Editor: Eric Bernhard, National Cancer Institute, United States of
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An induced pocket for the binding of potent fusion inhibitor CL-385319 with H5N1 influenza virus hemagglutinin.

... membrane fusion. This ‘‘induced fit’’ pocket may be a target for structure-based design of more potent influenza fusion inhibitors. Citation: Li R, Song D, Zhu Z, Xu H, Liu S (2012) An Induced Pocket for the Binding of Potent Fusion Inhibitor CL-385319 with H5N1 Influenza Virus Hemagglutinin. PLoS ONE 7(8): e41956. doi:10.1371/journal.pone.0041956 Editor: ... the RMSD of the protein backbone and inhibitor atoms stabilized around 1.50 A˚ from 50 ns to 75 ns, and the variation is within 1.0 A˚ . To further validate the equilibrium, we also analyzed the total energy (ETOT), potential energy (EPTOT), temperature (TEMP) and kinetic energy (EKTOT) fluctuations of the proteininhibitor complex during the MD simulations ... fusogenic pH [14]. However, until now, these ionic residues had not been correlated with properties of influenza fusion inhibitors. Therefore, understanding how CL385319 stabilizes HA could provide a clue for the development of new influenza fusion inhibitors. In H5N1-typed HA2, E1032, E1052, R1062 and T1072 are located in the stem region which experienced different
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Computational study on the inhibitor binding mode and allosteric regulation mechanism in hepatitis C virus NS3/4A protein.

... protein autoinhibited conformation via binding of allosteric inhibitors, such as 4VA studied in this work (Figure 1), could have the ability to inhibit both the helicase and protease enzymatic functions of the protein [11,12]. Allosteric inhibitor 4VA is different from existing protease inhibitors in their physical properties, nonpeptidic nature and ... energy decomposition analysis are also wildly used to predict the binding affinities of the inhibitor upon protein and to identify the key protein residues responsible for the binding of an inhibitor, which are useful for the structure based drug design of new potent inhibitors [24–34]. In the present study, we have utilized a combination of computational ... protein inhibitor bound protein apo protein (truncated) inhibitor bound protein(truncated) simulation time 100 ns 100 ns 100 ns 100 ns doi:10.1371/journal.pone.0087077.t001 PLOS ONE | starting structure X-ray structure of HCV NS3/4A protein (PDB ID code 1CU1) X-ray structure of HCV NS3/4A protein complexed with inhibitor
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Functional analysis of a missense mutation in the serine protease inhibitor SPINT2 associated with congenital sodium diarrhea.

... in complex with its inhibitor hepatocyte growth factor activator inhibitor- 1. J Biol Chem 288: 11155–11164. 50. Shia S, Stamos J, Kirchhofer D, Fan B, Wu J, et al. (2005) Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor1 B. J Mol Biol ... Kito M, et al. (1997) Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J Biol Chem 272: 6370–6376. 16. Lin CY, Anders J, Johnson M, Dickson RB (1999) Purification and characterization of a complex containing matriptase and a Kunitz-type serine protease inhibitor from human milk. J Biol Chem 274: 18237–18242. 17. ... human placental bikunin, a novel serine protease inhibitor containing two Kunitz domains. J Biol Chem 272: 12202–12208. 19. Kawaguchi T, Qin L, Shimomura T, Kondo J, Matsumoto K, et al. (1997) Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor. J Biol Chem 272: 27558–27564. 20. Muller-Pillasch
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The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

... uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effortrelated deficits observed in depressed patients. Citation: Randall PA, Lee CA, Nunes EJ, Yohn SE, Nowak V, et al. (2014) The VMAT-2 Inhibitor ... vehicle control for MSX-3. The catecholamine uptake inhibitor bupropion hydrochloride (Alfa Aesar, Ward Hill, MA) and the MAO-B inhibitor deprenyl hydrochloride (Tocris Bioscience) were dissolved in 0.9% saline, which also served as the vehicle control for these studies. The catechol O-methyl transferase (COMT) inhibitor tolcapone (Toronto Research Chemicals, ... AM4113). Finally, several putative and established antidepressant drugs (the adenosine A2A antagonist MSX-3, the catecholamine uptake blocker bupropion, the MAO-B inhibitor deprenyl, and the COMT inhibitor tolcapone) were assessed for their ability to reverse the effects of TBZ. This work was conducted in order to work towards the development of animal
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A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

... using a 1-mL pipette tip. While using the wound healing assay to measure changes in cell migration (Fig. 2A–B), we found that the inhibitory effect of apoEdp on HUVEC migration is dose dependent at the range of 6–100 mM; the 50% inhibitory concentration (IC50) for this assay is approximately 21.5 mM. (Fig. 2C). Figure 1. ApoEdp affects HUVEC survival ... Ferro V (2008) Synthesis and heparanase inhibitory activity of sulfated mannooligosaccharides related to the antiangiogenic agent PI-88. Bioorg Med Chem 16: 699–709. 53. Dredge K, Hammond E, Davis K, Li CP, Liu L, et al. (2010) The PG500 series: novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy. Invest ... radiotherapy, they are often associated with clinical side effects, and limited tumor regression [6]. Therefore, there has been an increased focus toward development of novel angiogenesis inhibitors and novel approaches to maximize the anti-angiogenic therapies [7]. Human apolipoprotein E (apoE) is one of the most frequently studied proteins known to be involved
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A computational approach to analyze the mechanism of action of the kinase inhibitor bafetinib.

... imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCRABL gene amplification. Int J Cancer 122: 2621–2627. 51. Kantarjian H, Coutre PL, Cortes J, Pinilla-Ibarz J, Nagler A, et al. (2010) Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia ... and functional genomics that dasatinib, a broad-spectrum kinase inhibitor, leads to apoptosis in lung cancer cells via inhibition of SRC, EGFR, FYN and, notably, LYN [47]. Therefore, it is possible that also bafetinib might have a pro-apoptotic effect on these cells as it is also a potent inhibitor of LYN. While expression of dasatinib-insensitive gatekeeper ... potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106: 3948–3954. 21. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, et al. (2007) Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 25: 1035–1044. 22. Ong SE,
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