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Letteratura scientifica selezionata sul tema "Dual inhibitors"

Autore: Grafiati

Pubblicato: 24 agosto 2024

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Articoli di riviste sul tema "Dual inhibitors"

Sipos, Ádám, Eszter Szennyes, Nikolett Éva Hajnal, Sándor Kun, Katalin E. Szabó, Karen Uray, László Somsák, Tibor Docsa e Éva Bokor. "Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors". Pharmaceuticals 14, n. 4 (15 aprile 2021): 364. http://dx.doi.org/10.3390/ph14040364.

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A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.

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Gesinski, Dayna, e Sonali Kurup. "Abstract 5337: Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5337. http://dx.doi.org/10.1158/1538-7445.am2023-5337.

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Abstract Mutant epidermal growth factor receptor (mEGFR) inhibitors constitute the recommended therapy for mEGFR-positive cancers. However, resistance has developed to mEGFR inhibitors due to newer mutations within the enzyme pocket and redundant signaling pathways that bypass mEGFR inhibition. Recent studies have shown that resistance to mEGFR inhibitors could be overcome if given in combination with aurora kinase (AURK) inhibitors. Dual EGFR/AURK kinase inhibitors provide a novel approach to overcome resistance to EGFR inhibitors. In a previous study, Kurup et al. identified 1 as a nanomolar mEGFR inhibitor. Using a structure-based design approach, novel analogs of 1 that incorporated varied sidechains for dual mEGFR and AURK inhibition were designed. The synthesis of the target compounds involved microwave-assisted, copper and palladium catalyzed coupling reactions. This study led to the identification of dual-targeted mEGFR/AURKA and mEGFR/AURKB inhibitors, and compounds with sub-micromolar cellular potencies. The design, synthesis, kinase inhibitory activities and anticancer effects of these novel analogs will be presented. Structure-activity relationships for mEGFR, AURKA and AURKB inhibition will be defined. Citation Format: Dayna Gesinski, Sonali Kurup. Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents. [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 5337.

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Kim, Min-Jeong, Sarita Pandit e Jun-Goo Jee. "Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments". Pharmaceuticals 15, n. 2 (16 febbraio 2022): 236. http://dx.doi.org/10.3390/ph15020236.

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A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 μM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs.

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Bošković, Jelena, Vladimir Dobričić, Marija Mihajlović, Jelena Kotur-Stevuljević e Olivera Čudina. "Synthesis, Evaluation of Enzyme Inhibition and Redox Properties of Potential Dual COX-2 and 5-LOX Inhibitors". Pharmaceuticals 16, n. 4 (6 aprile 2023): 549. http://dx.doi.org/10.3390/ph16040549.

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Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (1–13) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as N-hydroxyurea derivatives (1, 2 and 3), 3,5-di-tert-butylphenol derivatives (4, 5, 6, 7 and 13), urea derivatives (8, 9 and 10) and “type B hydroxamic acids” (11 and 12). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (1, 2, 3, 5, 6, 11 and 12) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors 1, 3, 5, 11 and 12 showed good antioxidant properties.

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Wang, Q. May, Robert B. Johnson, Louis N. Jungheim, Jeffrey D. Cohen e Elcira C. Villarreal. "Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides". Antimicrobial Agents and Chemotherapy 42, n. 4 (1 aprile 1998): 916–20. http://dx.doi.org/10.1128/aac.42.4.916.

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ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.

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Lu, Haiying, Lan Bai, Yanping Zhou, Yongping Lu, Zhongliang Jiang e Jianyou Shi. "Recent Study of Dual HDAC/PARP Inhibitor for the Treatment of Tumor". Current Topics in Medicinal Chemistry 19, n. 12 (30 luglio 2019): 1041–50. http://dx.doi.org/10.2174/1568026619666190603092407.

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The occurrence and development of tumors are closely related to epigenetic instability which modulates gene expression through DNA methylation, histone modification, chromatin remodeling, and RNA-related silencing. Histone deacetylase (HDAC) and poly (ADP-ribose) polymerase (PARP) are targets of epigenetic regulation. Over the years, a large number of studies have shown that HDAC inhibitors and PARP inhibitors have synergistic effects in the treatment of tumors, and there are reports of related dual HDAC/PARP inhibitors. This review will give a brief summary of the synergistic mechanisms of HDAC inhibitors and PARP inhibitors and introduce the design of the first dual HDAC/PARP inhibitor, which may guide the design of more dual HDAC/PARP inhibitors for the treatment of tumors.

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Wen, Hui, Wen Qin, Guangzhong Yang e Yanshen Guo. "Design and Synthesis of Arylamidine Derivatives as Serotonin/Norepinephrine Dual Reuptake Inhibitors". Molecules 24, n. 3 (30 gennaio 2019): 497. http://dx.doi.org/10.3390/molecules24030497.

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To improve the in vivo antidepressant activity of previously reported serotonin (5-HT) and norepinephrine (NE) dual reuptake inhibitors, three series of arylamidine derivatives were designed and synthesized. The in vitro 5-HT and NE reuptake inhibitory activities of these compounds were evaluated, and compound II-5 was identified as the most potent 5-HT (IC50 = 620 nM) and NE (IC50 = 10 nM) dual reuptake inhibitor. Compound II-5 exhibited potent antidepressant activity in the rat tail suspension test and showed an acceptable safety profile in a preliminary acute toxicity test in mice. Our results show that these arylamidine derivatives exhibit potent 5-HT/NE dual reuptake inhibition and should be explored further as antidepressant drug candidates.

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Vest, Rebekah S., Kurtis D. Davies, Heather O'Leary, J. David Port e K. Ulrich Bayer. "Dual Mechanism of a Natural CaMKII Inhibitor". Molecular Biology of the Cell 18, n. 12 (dicembre 2007): 5024–33. http://dx.doi.org/10.1091/mbc.e07-02-0185.

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Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of cellular Ca2+ signaling. Several inhibitors are commonly used to study CaMKII function, but these inhibitors all lack specificity. CaM-KIIN is a natural, specific CaMKII inhibitor protein. CN21 (derived from CaM-KIIN amino acids 43–63) showed full specificity and potency of CaMKII inhibition. CNs completely blocked Ca2+-stimulated and autonomous substrate phosphorylation by CaMKII and autophosphorylation at T305. However, T286 autophosphorylation (the autophosphorylation generating autonomous activity) was only mildly affected. Two mechanisms can explain this unusual differential inhibitor effect. First, CNs inhibited activity by interacting with the CaMKII T-site (and thereby also interfered with NMDA-type glutamate receptor binding to the T-site). Because of this, the CaMKII region surrounding T286 competed with CNs for T-site interaction, whereas other substrates did not. Second, the intersubunit T286 autophosphorylation requires CaM binding both to the “kinase” and the “substrate” subunit. CNs dramatically decreased CaM dissociation, thus facilitating the ability of CaM to make T286 accessible for phosphorylation. Tat-fusion made CN21 cell penetrating, as demonstrated by a strong inhibition of filopodia motility in neurons and insulin secrection from isolated Langerhans' islets. These results reveal the inhibitory mechanism of CaM-KIIN and establish a powerful new tool for dissecting CaMKII function.

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Lambert, Que T., Stuart W. Ember, Muhammad Ayaz, Harshani R. Lawrence, Norbert Berndt, Steven Gunawan, Nicholas J. Lawrence, Ernst Schönbrunn e Gary W. Reuther. "Single Molecule Dual JAK2-BET Inhibition As an MPN Therapeutic". Blood 126, n. 23 (3 dicembre 2015): 2826. http://dx.doi.org/10.1182/blood.v126.23.2826.2826.

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Abstract The optimism of anti-JAK2 therapy for the treatment of MPNs is largely based on the ability of JAK inhibitors to improve MPN patient constitutional symptoms. Unfortunately, such inhibitors are generally unable to induce remission or even allele burden, suggesting anti-JAK2 based therapies need refinement and optimization. Combination therapies continue to be widely investigated, however, such approaches could have significant complications when translating to patients. These include the difficulty determining proper dosing of each drug in combination in patients, the cost of treatment, and issues with combining drugs developed by different pharmaceutical companies. Recently, we and others have identified anti-BET bromodomain inhibitory properties of various kinase inhibitors, including the JAK2 inhibitors TG101209 and TG101308. Bromodomains are protein-protein interaction motifs that bind to acetylated lysine and, for example, can play roles in regulating gene expression by binding acetylated histones. These dual kinase-BET inhibitors bind to the acetylated lysine-binding pocket of BET bromodomains and thus inhibit the function of such domains. Importantly, cancer cells appear to be particularly sensitive to BET inhibitors compared to normal cells. Combining a BET inhibitor and a JAK2 inhibitor has been shown to be more effective against MPN cells than JAK2 inhibition alone. Our recent identification of dual kinase-BET inhibitors allows for the rational design of drugs with polypharmacology to inhibit more than one class of targets. To this end, we have optimized small molecules for dual anti-JAK2 and anti-BET activity. MA2-014 is a chemical derivative of TG101209 that exhibits similar anti-JAK2 activity, but about ten-fold improved anti-BET activity than TG101209. In fact, the activity of MA2-014 to target BET domains is similar to the prototypical BET inhibitor JQ1. For example, the IC50s of MA2-014 and JQ1 against the second bromodomain of the BET family member BRD4 are each about 20 nM. MA2-014 retains comparable biochemical activity against JAK2 as TG101209 and ruxolitinib (IC50s of low single digit nM, ~0.5 to 3 nM). In MPN cells, however, the ability of MA2-014 to inhibit JAK2-V617F signaling in MPN cells, as measured by P-STAT5, is about ten-fold improved over TG101209, and is comparable to ruxolitinib. Likewise, the ability of MA2-014 to inhibit the expression of c-Myc, which is widely used as a biomarker for BET inhibition, is about ten-fold better than TG101209 in MPN cells. The IC50 for MA2-014 for growth of Uke1 MPN cells is about 200 nM, compared to 500 nM for TG101209. Taken together, these data suggest that MA2-014 is a dual JAK2-BET inhibitor that exhibits superior BET inhibitory activity with similar if not better cellular JAK2 inhibitory activity than TG101209. MA2-014 efficiently inhibited the erythropoietin independent erythroid colony formation of myeloid progenitors from MPN patients, which is a hallmark of these cells and is widely used to test MPN therapeutics. The IC50 of MA2-014 in this assay is 50 nM, essentially identical to ruxolitinib, the only FDA approved JAK2 inhibitor for MPNs. The IC50 of TG101209 to inhibit this colony formation of primary MPN cells is 200 nM, four times greater than MA2-014. Interestingly, JAK2-V617F-driven MPN model cells that are resistant to ruxolitinib retained sensitivity to MA2-014. The IC50s of ruxolitinib and MA2-014 against the growth of BaF3-JAK2-V617F cells are about 100 nM. However, the same cells that are resistant to ruxolitinib (IC50 >2000 nM) remain sensitive to MA2-014 (IC50 of 240 nM). Finally, in long-term culture assays, we have determined that JAK2-V617F driven MPN Uke1 cells are not able to become resistant to MA2-014 as readily as they do to TG101209 or ruxolitinib. These data suggest MA2-014 may be more resilient to drug resistance, the major hurdle in the clinical effectiveness of JAK2 inhibitors. Collectively, our work demonstrates that rationally-designed polypharmacology may be a novel approach to develop effective therapeutics for cancer, especially diseases that are driven by aberrant kinase signaling and are also sensitive to BET inhibition, as exemplified by MPNs. The use of such an optimized polypharmacologic therapeutic may provide the benefits of combination therapy with fewer complications associated with clinical development. Disclosures No relevant conflicts of interest to declare.

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Dyer, Richard D., e David T. Connor. "Dual Inhibitors Of Prostaglandin And Leukotriene Biosynthesis". Current Pharmaceutical Design 3, n. 5 (1997): 463–72. http://dx.doi.org/10.2174/138161280305221010095741.

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One of the most promising approaches for minimizing the side effects of nonsteroidal antiinflammatory drugs (NSAIDs) is to concurrently inhibit the activities of both 5-lipoxygenase (5-LO) and cyclooxygenase (CO). Many such dual inhibitors of prostaglandin (PG) and leukotriene (LT) production in vitro have been described but, despite intense pharmaceutical research efforts, the translation of this in vitro activity into in vivo efficacy has proven difficult. Chemical modification of one series of inhibitors, the 2,6-di-tert butylphenols, has provided a variety of dual inhibitors with antiinflammatory efficacy and superior gastrointestinal (GI) safety. Whereas optimization of the di-t-butylphenols for in vitro activity, inhibitory specificity, oral availability and antiinflammatory efficacy resulted in the identification of Cl-1004 and other clincal candidates, optimization of other chemical series typically resulted in dual inhibitors with potent in vitro effects but little in vivo activity. The development of several dual inhibitors, including tepoxalin, tebufelone and CI-986, has been limited by drug metabolism issues. Translation of the attractive preclinical antiinflammatory and safety profile of dual inhibitors to the clinical arena awaits the completion of thorough clinical studies, such as those currently underway with CI-1004.

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Tesi sul tema "Dual inhibitors"

Meschini, Elisa. "Purine-based dual inhibitors of CDK2 and CDK7". Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1363.

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Cyclin-Dependent Kinases (CDKs) play a fundamental role in eukaryotic cell cycle progression, particularly at cell cycle checkpoints, and are therefore important targets for anticancer drug discovery. Activation of CDK2 in complex with Cyclin A regulates entry into S phase of the eukaryotic cell cycle. CDK7, a dual-function enzyme, acts both as a CDK-Activating Kinase (CAK) and as a component of the general transcription factor TFIIH. However, experiments with MAT1-knockdown mice have shown that cell cycle arrest by CAK inhibition would not be detrimental for transcriptional activity in non-dividing cells, as CDK9 in complex with Cyclin T can perform transcriptional duties in the absence of TFIIH. Previous studies have resulted in the identification of NU6102 (1, IC50 mM = 0.005 (CDK2), 4.4 (CDK7)) as a potent and selective CDK2 inhibitor, and NU6247 (2, IC50 mM = 0.12 (CDK2), 0.23 (CDK7)) as an equipotent CDK2/7 inhibitor. It was shown that the sulfonamide group of 1 confers potency and selectivity for CDK2, whereas the pendant piperazinyl substituent of 2 diminishes CDK2 actvity whilst improving activity versus CDK7. S NH N N NH N O O O 2 N N AccordinglyAs part of the work described in the present thesis, sulfonamide 3 (IC50 mM = 0.012 (CDK2), 0.67 (CDK7)) was synthesised and found to be is a potent CDK2 inhibitor, but with some CDK7-inhibitory activity (IC50 mM = 0.012 (CDK2), 0.67 (CDK7)). Further elaboration of the side-chain function has enabled the development of structure-activity relationships (SARs), and the identification of purines (e.g. 4, IC50 mM = 2.6 (CDK2), 0.56 (CDK7)) exhibiting some selectivity for CDK7, albeit with a loss of potency. 4 Subsequent SAR studies conducted on 2 have enabled the following observations to be made: firstly, the purine 6-cyclohexylmethoxy substituent is necessary for activity, with the corresponding 6-unsubstituted purine (5, IC50 mM = 46.9 (CDK2), 20.8 (CDK7)) exhibiting a 100-fold loss of potency against both CDK2 and CDK7. A terminal basic group (e.g. piperazinyl in 2) is required for activity, as replacement by a cyclohexyl substituent results in loss of activity against both kinases (6, 11% inhibition at 10 mM (CDK2), 13% inhibition at 100 mM (CDK7)). The sulfone linker is not a prerequisite for CDK7 activity, with the simple alkylpiperazine derivative (7, IC50 mM = 0.48 (CDK2), 0.51 (CDK7)) exhibiting comparable potency and selectivity. Finally, there appears to be some opportunity for expansion into the gatekeeper pocket of CDK7 by introducing small substituents at the purine C-8 position, with the potential for selectivity over CDK2 (8, 47% inhibition at 100 mM (CDK2), IC50 = 5 mM (CDK7)). Isolation and biological evaluation of the vinyl sulfone 9, an intermediate in the synthesis of 2, indicated a time-dependent inhibition of CDK2, suggesting that 9 is an irreversible inhibitor of CDK2. This would be the first reported irreversible inhibitor of a cyclin-dependent kinase, and therefore the activity of the compound against CDK2 was investigated using protein crystallography and site-directed mutagenesis 5 techniques. From these studies, encouraging evidence has emerged that 9 acts as an irreversible inhibitor of CDK2, covalently binding to a lysine residue within the ATP-binding pocket.

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Green, Ian. "The biology of novel dual histone methyltransferase inhibitors". Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/25763.

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Background: EZH2 is a histone methyltransferase (HKMT) responsible for the maintenance of epigenetic silencing of genes through maintenance of the repressive H3K27me3 mark and it is aberrantly regulated in numerous cancers, including breast cancer where it is linked to aggressive phenotypes and poor clinical outcomes. EHMT2 is a related HKMT responsible for gene silencing by mediating H3K9me3 levels. EHMT2 is also responsible for H3K27me1 and has been shown to physically interact with EZH2. Specific inhibitors of EZH2 are available and have been shown to be effective in cancers with EZH2 mutation driven phenotypes (e.g. follicular lymphoma) but have shown limited efficacy in epithelial cancers. Here we present the characterisation of novel dual HKMT inhibitors targeting both EZH2 and EHMT2, which we believe will have a greater impact than individual inhibitors in reversing EZH2 mediated silencing. Results: Utilising publicly available data, we show expression of EZH2 and related subunits of the PRC2 complex and related EHMT2/EHMT1 complex range greatly in normal tissue, but EZH2 and EHMT2 expression are consistently up-regulated in numerous cancers. We show that CNV and mutation of EZH2 and EHMT2 infrequently occur in breast cancer- however, in breast cancer high expression of EZH2 is linked to reduced RFS and OS of patients. In breast cancer cell lines, dual HKMT inhibitors up-regulate EZH2 target genes, in gene specific and genome wide manner, to a greater degree than EZH2 or EHMT2 inhibition alone and induce expression of genes associated with apoptotic pathways. This up-regulation of silenced genes occurs concurrently with a decrease in H3K27me3 and H3K9me3 levels on target genes. In breast cancer cells and ovarian cancer cells, dual HKMT inhibitors reduce cell clonogenicity, cancer stem cell activity, cancer stem cell self-renewal capacity, and sensitise cancer stem cells to Paclitaxel and Cisplatin treatment. Conclusions: Novel dual inhibitors of EZH2 and EHMT2 alter gene expression and inhibit cell growth and cancer stem cell activity in wild-type EZH2 tumour cells. These data support the further preclinical and clinical evaluation of such inhibitors in triple negative breast cancer and epithelial ovarian cancer.

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Apsel, Beth. "Dual-specificity inhibitors of lipid and protein kinases". Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3311357.

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Ren, Baiping. "Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides". University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697.

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Wong, Jacky Sui Ki. "The Evaluation of Dual PI3K/mTOR Inhibitors as a Superior Alternative to mTOR Inhibitors in Pre-B Acute Lymphoblastic Leukaemia". Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13644.

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Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. Poor long term survival in adults as well as the bleak outlook for relapsed patients highlights the need for new therapeutic strategies for the treatment of ALL. The major regulators of ALL cell proliferation and survival mediate their effects through the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin. It has been previously shown that the mTOR inhibitor RAD001 extended survival in a non-obese diabetic/severe combined immune deficient (NOD/SCID) mouse xenograft model of ALL. The work presented in this thesis examines the effect of the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in ALL. In summary, dual PI3K/mTOR inhibitors demonstrate primarily superior cytostatic effects in vitro but a mixed level of cytotoxicity when compared to RAD001. In addition, the dual PI3K/mTOR inhibitors extended survival in NOD/SCID mice engrafted with ALL xenografts but failed to demonstrate overall superiority over mTOR inhibition alone. This work contributed to the publication of a paper, presented in two separate chapters. Subsequent unpublished work presented in this thesis examined the effects of the dual PI3K/mTOR inhibitors in combination with conventional chemotherapeutic agents. However, the results presented in this thesis indicate that the dual PI3K/mTOR inhibitors do not cooperate well with the tested agents. Furthermore, the cooperation observed with the dual PI3K/mTOR inhibitors in combination with a MEK inhibitor highlights the need to explore strategies to target multiple signalling pathways.

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Fraser, Sasha. "Development of Dual-Pathway Inhibitors of Raf/MEK/ERK and PI3K/Akt Signaling Pathways". VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2619.

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In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity.

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Steinemann, Gustav [Verfasser]. "Charakterisierung der Wirkmechanismen des neuartigen, dual wirksamen HDAC-Inhibitors „Animacroxam“ am Beispiel testikulärer Keimzelltumore / Gustav Steinemann". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1234984474/34.

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Tamhaev, Rasoul. "Conception, synthèse et caractérisation de dérivés diaryl éthers comme nouveaux inhibiteurs directs de la protéine InhA de Mycobacterium tuberculosis". Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://thesesups.ups-tlse.fr/6088/.

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La tuberculose, bien que maladie très ancienne, est toujours une des causes majeures de mortalité due à un agent infectieux unique. En 2021, 10 millions de personnes ont contracté la maladie et 1.5 millions de décès étaient directement imputables à cette dernière. Malgré la disponibilité de toute une panoplie d'antibiotiques, peu d'entre eux s'avèrent efficaces contre l'agent pathogène responsable de la tuberculose, Mycobacterium tuberculosis. Cette inefficacité est principalement due au caractère imperméable de l'enveloppe cellulaire mycobactérienne, composée majoritairement d'acides mycoliques. L'isoniazide, l'antituberculeux de première ligne le plus utilisé, cible la biosynthèse de ces acides mycoliques via la protéine InhA. L'isoniazide agit comme une pro-drogue nécessitant une activation par la protéine KatG. Cependant, l'émergence de résistances lors de l'étape d'activation de l'isoniazide implique la nécessité de développer des inhibiteurs directs d'InhA. Les travaux réalisés durant cette thèse avaient pour objectif de développer de nouveaux inhibiteurs directs d'InhA. Ces derniers ont été développés autour de la structure d'un motif diaryl éther, connu pour sa capacité à inhiber l'enzyme. La chimie combinatoire dynamique combinée à la cristallographie aux rayons X a été utilisée comme méthode de criblage de fragments pour découvrir de nouveaux inhibiteurs. Trois adduits, visualisés directement à l'intérieur du site actif de la protéine, ont ainsi été caractérisés et montrent des interactions avec le portail majeur de la protéine. Dans un autre projet, une nouvelle famille de diaryl éthers comportant trois pharmacophores a été conçue afin d'occuper entièrement le site de liaison du substrat. Une des molécules synthétisées possède une activité inhibitrice inférieure au micromolaire contre InhA. La structure du complexe correspondant a été résolue par cristallographie aux rayons X, mettant en évidence une ouverture inédite d'une des régions de la protéine, appelée portail mineur. Enfin, des approches multi-cibles, ciblant à la fois InhA et le complexe déshydratase HadABC du système FAS II, ont également été développées durant cette thèse. Plusieurs molécules duales ont été produites et montrent une inhibition de l'activité d'InhA de l'ordre du nanomolaire. Ces molécules montrent également une inhibition de la croissance de différentes souches mycobactériennes
Tuberculosis, despite being a very ancient disease, remains one of the major causes of mortality due to a single infectious agent. In 2021, 10 million people contracted the disease and 1.5 million deaths were directly attributable to it. Despite the availability of a variety of antibiotics, few of them prove effective against the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. This ineffectiveness is primarily due to the impermeable nature of the mycobacterial cell envelope, composed mainly of mycolic acids. Isoniazid, the most widely used first-line antitubercular drug, targets the biosynthesis of these mycolic acids through the protein InhA. Isoniazid acts as a pro-drug requiring activation by the protein KatG. However, the emergence of resistance during the activation stage of isoniazid necessitates the development of direct inhibitors of InhA. The work carried out during this thesis aimed to develop new direct inhibitors of InhA. These inhibitors were designed basedon the structure of a diaryl ether motif, known for its ability to inhibit the enzyme. Dynamic combinatorial chemistry combined with X-ray crystallography was used as a fragment screening method to discover new inhibitors. Three adducts, visualized directly within the active site of the protein, were characterized and showed interactions with the major portal of the protein. In another project, a new family of diaryl ethers with three pharmacophores was designed to fully occupy the substrate binding site. One of the synthesized molecules exhibited sub-micromolar inhibitory activity against InhA. The structure of the corresponding complex was resolved by X-ray crystallography, highlighting a wider opening of one of the protein's regions, called the minor portal. Finally, multi-target approaches, targeting both InhA and the dehydratase complex HadABC of the FAS II system, were also developed during this thesis. Several dual molecules were produced, showing inhibition of InhA activity in the nanomolar range. These molecules also demonstrated inhibition of the growth of different mycobacterial strains

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Yule, Ian Andrew. "Design, synthesis and biological evaluation of novel, dual targeting inhibitors of bacterial DNA gyrase and topoisomerase IV". Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713881.

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The inevitability of bacterial drug resistance to all marketed antibiotic drug classes warrants continual research into the development of novel chemotype antibacterial agents. Drug resistant `superbugs' such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE) account for >70% of US hospital bound bacteremias. Such infections are associated with vastly increased rates of morbidity and mortality resulting in a heavy economic burden on health care authorities. The bacterial topoisomerase enzymes DNA gyrase and topoisomerase IV are highly conserved amongst almost all bacterial species on account of their unique and essential function in the conservation of chromosomal integrity during DNA replication and transcription. Furthermore, structural similarity between gyrase and topo IV, and distinction from human homologues, makes the selective dual-inhibition of these enzymes a realistic goal. In this thesis, three distinct approaches were utilized in the discovery of novel inhibitors of gyrase (GyrB) and topoisomerase IV (ParE) acting at the ATP binding domains of these enzymes. In the initial strategy, structural variants based on known inhibitors were modelled within the GyrB ATPase site in a bid to displace a highly conserved water molecule at the ligand-enzyme interface. Synthesis and biological screening of these variants proved that such changes were to the detriment of activity, although the work did yield a novel, convenient preparation of Nsubstituted thieno[2,3-d]pyrimidinones. In an alternative strategy, the de novo molecular design software SPROUT was used in concert with crystallographic data on the GyrB ATP binding site. Putative inhibitors were thus generated 'from scratch', the most attractive of which were further modelled using docking software (AUTODOCK), synthesised and screened for enzyme inhibitory and antimicrobial activity. A number of early series were derived which demonstrated modest (GyrB IC50 <100 μM) enzyme activity. The most promising of these, a series of pyridine-3-carboxamides, was optimized to offer potent (GyrB IC50 <100 nM) enzyme inhibitory activity, dual target specific antibacterial activity (MICs <0.5 μg / mL) and a low potential for resistance development. Finally, using the GLIDE docking software, virtual compound libraries were screened in silico against the ATP binding domain of GyrB. Though largely unsuccessful, the process did identify a moderate inhibitor (GyrB IC50 118 μM, MIC 32 μg / mL), in a cost and time effective manner relative to high-throughput screening.

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Foka, Germaine Boulenoue. "Synthesis and evaluation of novel coumarin-donepezil derivatives as dual acting monoamine oxidase B and cholinesterase in Alzheimer's disease". University of the Western Cape, 2016. http://hdl.handle.net/11394/5549.

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Magister Pharmaceuticae - MPharm
Alzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity.
National Research Foundation (NRF)

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Libri sul tema "Dual inhibitors"

Shepherd, Angela J., e Juliet M. Mckee. Osteoporosis. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190466268.003.0015.

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Osteoporotic fractures are major causes of suffering and death. Dual-energy x-ray absorptiometry (DEXA) is the standard of care for diagnosis (T-score ≤ –2.5) of osteoporosis. Prevention of fractures requires addressing bone and muscle strength and balance. Physical exercise, good nutrition (fruits, vegetables, adequate calcium), adequate vitamin intake (C, D, and K), tobacco cessation, and no more than moderate alcohol intake enhance bone health and decrease fracture risk. Long-term treatment with glucocorticoids, certain drugs used in breast or prostate cancer treatment, and proton pump inhibitors used for gastroesophageal reflux disease may increase the risk for osteoporosis. Pharmacologically, bisphosphonates are the mainstay of osteoporosis treatment.

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Kuwabara, Satoshi. Neuromuscular junction disorders. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199658602.003.0014.

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Ten seminal papers on disorders of the neuromuscular junction are described, covering historical aspects, recent advances in immunological, biological, and genetic researches, and future perspectives. Early descriptions of myasthenia gravis (MG) date back to the seventeenth century, and MG acquired its name in the nineteenth century. The first symptomatic treatment with cholinesterase inhibitors was reported in 1934, leading to the development of modern immunological therapies. Following the discovery of anti-MuSK (muscle-specific tyrosine kinase) antibody in 2001, MG is currently classified into three categories: AChR-positive, MuSK-positive, and dual-seronegative. Lambert-Eaton myasthenic syndrome was recognized in 1956, followed by the discovery of antibodies to voltage-gated calcium channels in the pre-synaptic membrane, facilitating diagnosis and improving the understanding of the pathophysiological mechanisms. Since the late twentieth century, many types of congenital myasthenic syndromes with pre-synaptic, synaptic, and post-synaptic defects have been identified, and a classification based on molecular genetics is in evolution.

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Ferro, Charles J., e Khai Ping Ng. Recommendations for management of high renal risk chronic kidney disease. A cura di David J. Goldsmith. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0099.

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Poorer renal function is associated with increasing morbidity and mortality. In the wider population this is mainly as a consequence of cardiovascular disease. Renal patients are more likely to progress to end-stage renal disease, but also have high cardiovascular risk. Aiming to reduce both progression of renal impairment and cardiovascular disease are not contradictory. Focusing on the management of high-risk patients with proteinuria and reduced glomerular filtration rates, it is recommended that blood pressure should be kept below 140/90, or 130/80 if proteinuria is > 1 g/24 h (protein:creatinine ratio (PCR) >100 mg/mmol or 0.9 g/g). These targets may be modified according to age and other factors. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor antagonists should form part of the therapy for patients with proteinuria > 0.5 g/24 h (PCR > 50 mg/mmol or 0.45 g/g). Use of ACEIs or angiotensin receptor blockers in patients with lower levels of proteinuria may be indicated in some patient groups even in the absence of hypertension, notably in diabetic nephropathy. Evidence that other agents that reduce proteinuria bring additional benefits is weak at present. The best studies of ‘dual-blockade’ with various combinations of ACEIs, ARBs, and renin inhibitors have shown additional hazard with little evidence of additional benefit. Hyperlipidaemia—regardless of lipid levels, statin therapy is indicated in secondary cardiovascular prevention, and in primary prevention where cardiovascular risk is high, noting that current risk estimation tools do not adequately account for the increased risk of patients with CKD. There is not substantial evidence that lipid lowering therapy impacts on average rates of loss of GFR in progressive CKD. Non-drug lifestyle interventions to reduce cardiovascular risk, including stopping smoking, are important for all. Acidosis—in more advanced CKD it is justified to treat acidosis with oral sodium bicarbonate. Diet—sodium restriction to < 100 mmol/day (6 g/day) and avoidance of excessive dietary protein are justified in early to moderate CKD. Recommendations to limit levels of protein to 0.8 g/kg body weight are suggested by some, but additional protective effects of this are likely to be slight in patients who are otherwise well managed. Low-protein diets may carry some risk. Lower-protein diets may however be used to prevent symptoms in advanced CKD not treated by dialysis.

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Castellanos, Madeleine M. Female Sexual Biochemistry (DRAFT). A cura di Madeleine M. Castellanos. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190225889.003.0001.

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“Female Sexual Biochemistry” reviews the key hormones and neurotransmitters that have a major role in female sexuality. Estrogens—estradiol, estrone, and estriol—as well as major androgens, such as testosterone and dihydrotestosterone (DHT), are presented with a discussion of their role in the support of the reproductive organs and genitals as well as their actions on the central nervous system to affect sexual desire, arousal, and responsiveness. The interaction and regulation of estrogen by progesterone and thyroid hormone is included. A review of the dual-control model of sexual responsiveness is presented, including excitatory and inhibitory factors, as well as a summary of major neurotransmitters that work to enhance sexual arousal or inhibit it. The sexual response cycle is reviewed and relevant changes in pregnancy, childbirth, perimenopause, and menopause are presented. Finally, there is mention of how synthetic hormones and environmental toxins with hormone activity may alter a woman’s sexual response.

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Bueno, Héctor, e José A. Barrabés. Non-ST-segment elevation acute coronary syndromes. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199687039.003.0046.

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Non-ST-segment elevation acute coronary syndromes are life-threatening disorders, usually caused by acute coronary thrombosis and subsequent myocardial ischaemia, presenting without persistent ST-segment elevation in the initial electrocardiogram. According to the occurrence of myocardial necrosis, non-ST-segment elevation acute coronary syndromes are divided into non-ST-segment myocardial infarction or unstable angina. The management of non-ST-segment elevation acute coronary syndromes requires an early diagnosis and risk stratification, urgent hospitalization, monitoring, and medical treatment, including antithrombotic therapy with dual antiplatelet therapy (aspirin plus one P2Y12 inhibitor) and parenteral anticoagulation, anti-ischaemic treatment, and preventative therapies. After the initial medical therapy is established, an invasive strategy, consisting of coronary angiography with coronary revascularization (either percutaneous coronary intervention or coronary bypass graft surgery), as appropriate, should be decided. The timing of the invasive strategy should be adjusted, according to the patient’s risk. Given the high event rate of patients with non-ST-segment elevation acute coronary syndromes after hospital discharge, an aggressive long-term preventative therapy should be put in place to improve prognosis.

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Bueno, Héctor, e José A. Barrabés. Non-ST-segment elevation acute coronary syndromes. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199687039.003.0046_update_001.

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Bueno, Héctor, e José A. Barrabés. Non-ST-segment elevation acute coronary syndromes. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199687039.003.0046_update_002.

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Pirani, Tasneem, e Tony Rahman. Diagnosis and management of upper gastrointestinal haemorrhage in the critically ill. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0177.

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Upper gastrointestinal haemorrhage is a medical emergency that may present with haematemesis and/or melena. An exhaustive history and careful examination aids in identifying the cause of bleeding and directing appropriate management. Validated scoring systems exist to guide the urgency of endoscopic therapy, although these should not be used in isolation, but in conjunction with complete patient assessment. The initial priority should be to resuscitate and stabilize the patient using the airway, breathing, circulation, and disability framework. Resuscitation should be guided by clinical and physiological parameters. Patients should be managed in an environment where vital signs such as heart rate, blood pressure, respiratory rate, conscious level, and urine output are monitored at least hourly. Attempts should be made to correct coagulopathy. Specialist advice should be sought from haematologists for guidance on the most appropriate use of packed red cells and blood products. Over-transfusion should be avoided. Initiation of pre-endoscopy proton pump inhibitor therapy, in particular to avoid definitive endoscopic therapy, is not recommended. Diagnostic endoscopy and therapy should be conducted within 24 hours of presentation. Numerous endoscopic therapies exist—when epinephrine is used for local tamponade and vasoconstriction, application of dual modality treatment is recommended. In cases where endoscopic therapy fails or is not possible, radiological diagnosis, and embolization may become necessary. Occasionally, surgery is required for definitive treatment—close liaison with surgeons is therefore necessary, especially where initial endoscopy is considered suboptimal or re-bleeding occurs.

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Capitoli di libri sul tema "Dual inhibitors"

Fink, Cynthia A. "Dual inhibitors of angiotensin converting enzyme and neutral endopeptidase". In ACE Inhibitors, 155–62. Basel: Birkhäuser Basel, 2001. http://dx.doi.org/10.1007/978-3-0348-7579-0_11.

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Frye, Leah L., e Deborah A. Leonard. "Dual-Action Inhibitors of Cholesterol Biosynthesis". In ACS Symposium Series, 94–108. Washington, DC: American Chemical Society, 1992. http://dx.doi.org/10.1021/bk-1992-0497.ch009.

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Trapencieris, Peteris, Anete Parkova e Ineta Vendina-Birzniece. "Carbonic Anhydrase Inhibitors with Dual Targeting". In Carbonic Anhydrase as Drug Target, 163–78. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-12780-0_12.

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Fong, Alan Yean Yip, e Hwei Sung Ling. "Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI". In Primary Angioplasty, 99–108. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1114-7_8.

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Anighoro, Andrew, Luca Pinzi, Giulio Rastelli e Jürgen Bajorath. "Virtual Screening for Dual Hsp90/B-Raf Inhibitors". In Methods in Pharmacology and Toxicology, 355–65. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/7653_2017_1.

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Wang, Huan, e Chao Wang. "Peptide-Based Dual HIV and Coronavirus Entry Inhibitors". In Advances in Experimental Medicine and Biology, 87–100. Singapore: Springer Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-8702-0_6.

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Albanell, J. "Dual/Pan-Her Tyrosine Kinase Inhibitors: Focus in Breast Cancer". In New trends in cancer for the 21st century, 329–40. Dordrecht: Springer Netherlands, 2006. http://dx.doi.org/10.1007/978-1-4020-5133-3_25.

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Karlsson, Andreas, e Carlos García-echeverría. "Chapter 13. Identification and Optimization of Dual PI3K/mTOR Inhibitors". In Drug Discovery, 206–20. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849734912-00206.

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Sica, Domenic A. "Dual Inhibitors: RAAS Blockers/Combination Therapies: What Do All These Trials Mean?" In Chronic Kidney Disease and Hypertension, 57–68. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1982-6_6.

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Giembycz, Mark A., e Robert Newton. "Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies". In Phosphodiesterases as Drug Targets, 415–46. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-17969-3_18.

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Atti di convegni sul tema "Dual inhibitors"

Chang, Wenteh, Ke Wei e Glenn Rosen. "Suppression Of Lung Fibrosis By Dual MTOR Inhibitors". In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a2718.

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Quinn, Elizabeth R., Pietro Ciceri, Susanne Müller-Knapp, Alison O'Mahony, Oleg Fedorov, Panagis Filippakopoulos, Jeremy P. Hunt et al. "Abstract 5387: Dual kinase/bromodomain inhibitors for rationally designed polypharmacology". In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-5387.

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Keta, Otilija, Jelena Bošković, Vladana Petković, Neda Đorđević, Vladimir Dobričić, Olivera Čudina e Snežana B. Pajović. "Synthesis and cytotoxic activity of selected dual COX-2 and 5-LOX inhibitors in HeLa and MIA PaCa-2 human cancer cell lines". In 2nd International Conference on Chemo and Bioinformatics. Institute for Information Technologies, University of Kragujevac, 2023. http://dx.doi.org/10.46793/iccbi23.503k.

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Among novel cancer chemotherapy approaches, the use of cyclooxygenases (COXs) and lipoxygenases (LOXs) inhibitors represents a promising mean for cancer treatment showing lesser toxicity comparing to the currently used cytotoxic drugs. This study detailed the synthesis of three novel compounds: 1ME, BHTK-AA, and IBU-Ac, each with the capability to concurrently inhibit both COX-2 and 5-LOX. Subsequently, we assessed their effectiveness in inhibiting the proliferation of HeLa cervical and MIA PaCa-2 pancreatic cancer cells. The IC50 values for both examined cell lines were approximately 40 μM, indicating the promising inhibitory potential of the IBU-Ac compound in both types of cancer cells. This finding is positioned to stimulate further investigation into the potential application of IBU-Ac against these particular types of cancers, while also advocating its use in combination with standard anti-cancer protocols, i.e., chemoterapeutics or radiation therapy. The results of this work are also advocating the development and refinement of dual COX-2 and 5-LOX inhibitors, thus improving their efficacy and safety.

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Chang, Lei, Peter Graham, Jingli Hao, Jie Ni, Joseph Bucci, Paul Cozzi, John Kearseley e Yong Li. "Abstract A283: PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a283.

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Hannon, C. L., J. Gerstmann, F. B. Mansfeld e Z. N. Sun. "Development of Improved Corrosion Inhibitors for Ammonia-Water Absorption Heat Pumps". In ASME 2000 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2000. http://dx.doi.org/10.1115/imece2000-1294.

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Abstract This paper describes the initial results of a research project to develop an improved corrosion inhibitor for the protection of carbon steel surfaces of ammonia-water absorption heat pumps and chillers using rare earth metal salt (REMS) compounds. Chromate compounds are currently used as corrosion inhibitors, but they are toxic, environmentally harmful, and their use is being phased out in many localities. An effective corrosion inhibitor is needed to make advanced ammonia-water absorption heat pump and chiller systems practical. Low-temperature screening tests were conducted to evaluate the potential of cerium salts, a class of REMS compounds, to act as an inhibitor for steel in ammonia-water solutions. Successful results from these tests led to high-temperature (HT) testing in an innovative test apparatus, which simulated a range of temperatures, ammonia concentrations, and phases typically found in ammonia-water absorption systems. HT testing further demonstrated the effectiveness of cerium nitrate as a corrosion inhibitor, and suggested that it may outperform the Chromate compounds currently used. An additional outcome of the project was the successful demonstration of a cerium based surface pretreatment procedure, termed cerating, as an additional corrosion protection feature. Cerated surfaces will prevent corrosion of steel surfaces and ammonia decomposition at steel surfaces. These results have lead to the concept of a dual corrosion protection strategy utilizing a cerium based solution inhibitor with a cerating surface pretreatment to prevent both corrosion and ammonia decomposition. This approach is presently being pursued in a more intensive study.

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Hannon, C. L., J. Gerstmann, F. B. Mansfeld e Z. Sun. "Development of Corrosion Inhibitors for Absorption Heat Pumps". In ASME 2002 International Mechanical Engineering Congress and Exposition. ASMEDC, 2002. http://dx.doi.org/10.1115/imece2002-33411.

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This paper describes the results of a research project to develop a non-toxic corrosion in hibitor for the protection of carbon steel surfaces of ammonia-water absorption heat pumps through the use of rare earth metal salt (REMS) compounds. Chromate compounds are currently used as corrosion inhibitors in these systems, but are toxic, environmentally harmful, and their use is being phased out. Corrosion concerns in ammonia-water absorption systems are primarily those of non-condensable (NC) gases generated by corrosion reactions impeding the heat and mass transfer processes in the system. The research focused on the development of a dual-protection REMS based strategy of applying a cerium-oxide/hydroxide coating to the metal surface in a process called cerating, in conjunction with a cerium-sulfate solution-based inhibitor. A laboratory test was conducted in test rigs designed to simulate the conditions of temperature and ammonia concentration found in the desorber component of advanced ammonia-water absorption systems. The test compared the NC gas generation rate in a rig with cerated steel surfaces to a rig using sodium chromate as a solution based inhibitor. The cerated test rig demonstrated an NC gas generation rate about 3 times lower than that of the chromate protected rig. Neither rig showed any indications of significant corrosion activity. This work has shown that cerating can provide superior suppression of NC gas generation in ammonia-water absorption systems compared to sodium chromate, in a process that is simple and readily applicable to the commercial manufacture of equipment.

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Saunders, Nicholas A., Rafael Erlich, Zoulika Kherrouche, Mehlika Hazar-Rethinam, Lilia Merida de Long e Alexander Guminski. "Abstract 2559: Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma". In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2559.

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Chen, Chien-Yu, Fuu-Jen Tsai, Jing-Gung Chung, Chang-Hai Tsai, Yuan-Man Hsu, Hung-Jin Huang, Tin-Yun Ho et al. "A Novel Strategy for Designing Dual-Target Inhibitors of KU86 and XRCC4". In 2009 2nd International Conference on Biomedical Engineering and Informatics. IEEE, 2009. http://dx.doi.org/10.1109/bmei.2009.5302325.

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Sivanandhan, Dhanalakshmi, Sridharan Rajagopalan, Sreekala Nair, Purushottam Dewang, Durga Prasanna Kumar, Chandrika Mulakala, Lavanya Mahadevan et al. "Abstract 3509: Novel dual inhibitors of LSD1-HDAC for treatment of cancer". 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.am2015-3509.

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Taidi, Loubna, Amal Maurady e Rajae Chahboune. "Dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase with molecular docking study". In NISS 2023: The 6th International Conference on Networking, Intelligent Systems & Security. New York, NY, USA: ACM, 2023. http://dx.doi.org/10.1145/3607720.3607737.

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Rapporti di organizzazioni sul tema "Dual inhibitors"

Li, Pui-Kai. Development for Dual Acting Inhibitors for Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, agosto 2001. http://dx.doi.org/10.21236/ada398105.

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Li, Pui-Kai. Development of Dual Acting Inhibitors for Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, agosto 2002. http://dx.doi.org/10.21236/ada410197.

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Li, Pui-Kai. Development of Dual Acting Inhibitors for Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, novembre 2004. http://dx.doi.org/10.21236/ada432232.

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Li, Pui K. Development of Dual Acting Inhibitors for Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, agosto 2003. http://dx.doi.org/10.21236/ada421903.

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Simeonova, Rumiana, Vessela Vitcheva, Ivanka Kostadinova, Iva Valkova, Irena Philipova, Georgi Stavrakov, Nikolai Danchev e Irini Doytchinova. In Vivo Studies on Novel Potent Acetylcholinesterase Inhibitors with Dual-site Binding for Treatment of Alzheimer’s Disease. "Prof. Marin Drinov" Publishing House of Bulgarian Academy of Sciences, giugno 2021. http://dx.doi.org/10.7546/crabs.2021.06.13.

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Chagas, Gabriel, Rafael Chagas e Amanda Rangel. Effectiveness and Safety of Single Antiplatelet Therapy with P2Y12 Inhibitor Monotherapy versus Dual Antiplatelet Therapy After Percutaneous Coronary Intervention for Acute Coronary Syndrome: A Systematic Review and Meta-Analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, luglio 2022. http://dx.doi.org/10.37766/inplasy2022.7.0097.

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Review question / Objective: What are the effects of single antiplatelet therapy with P2Y12 inhibitor monotherapy versus dual antiplatelet therapy after percutaneous coronary intervention for acute coronary syndrome? Condition being studied: Antiplatelet therapy after percutaneous coronary intervention for acute coronary syndrome. Information sources: The databases will be Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (Embase), and Cochrane Library. Searches were conducted on July 25, 2022 and will be updated on August 25, 2022. There will be no language or publication period restrictions.

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Gao, Tong, Yintang Wang, Chang Meng, Siyuan Li, Lei Bi, Yu Geng e Ping Zhang. Aspirin Vs P2Y12 inhibitor monotherapy following dual antiplatelet therapy after coronary stenting in patients with ischemic heart disease: an updated systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, dicembre 2022. http://dx.doi.org/10.37766/inplasy2022.12.0011.

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Gafni, Yedidya, Moshe Lapidot e Vitaly Citovsky. Dual role of the TYLCV protein V2 in suppressing the host plant defense. United States Department of Agriculture, gennaio 2013. http://dx.doi.org/10.32747/2013.7597935.bard.

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TYLCV-Is is a major tomato pathogen, causing extensive crop losses in Israel and the U.S. We have identified a TYLCV-Is protein, V2, which acts as a suppressor of RNA silencing. Intriguingly, the counter-defense function of V2 may not be limited to silencing suppression. Our recent data suggest that V2 interacts with the tomato CYP1 protease. CYP1 belongs to the family of papain-like cysteine proteases which participate in programmed cell death (PCD) involved in plant defense against pathogens. Based on these data we proposed a model for dual action of V2 in suppressing the host antiviral defense: V2 targets SGS3 for degradation and V2 inhibits CYP1 activity. To study this we proposed to tackle three specific objectives. I. Characterize the role of V2 in SGS3 proteasomal degradation ubiquitination, II. Study the effects of V2 on CYP1 maturation, enzymatic activity, and accumulation and, III. Analyze the effects of the CYP1-V2 interaction on TYLCV-Is infection. Here we describe results from our study that support our hypothesis: the involvement of the host's innate immune system—in this case, PCD—in plant defense against TYLCV-Is. Also, we use TYLCV-Is to discover the molecular pathway(s) by which this plant virus counters this defense. Towards the end of our study we discovered an interesting involvement of the C2 protein encoded by TYLCV-Is in inducing Hypersensitive Response in N. benthamianaplants which is not the case when the whole viral genome is introduced. This might lead to a better understanding of the multiple processes involved in the way TYLCV is overcoming the defense mechanisms of the host plant cell. In a parallel research supporting the main goal described, we also investigated Agrobacteriumtumefaciens-encoded F-box protein VirF. It has been proposed that VirF targets a host protein for the UPS-mediated degradation, very much the way TYLCV V2 does. In our study, we identified one such interactor, an Arabidopsistrihelix-domain transcription factor VFP3, and further show that its very close homolog VFP5 also interacted with VirF. Interestingly, interactions of VirF with either VFP3 or VFP5 did not activate the host UPS, suggesting that VirF might play other UPS-independent roles in bacterial infection. Another target for VirF is VFP4, a transcription factor that both VirF and its plant functional homolog VBF target to degradation by UPS. Using RNA-seqtranscriptome analysis we showed that VFP4 regulates numerous plant genes involved in disease response, including responses to viral and bacterial infections. Detailed analyses of some of these genes indicated their involvement in plant protection against Agrobacterium infection. Thus, Agrobacterium may facilitate its infection by utilizing the host cell UPS to destabilize transcriptional regulators of the host disease response machinery that limits the infection.

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