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Covalent inhibitor

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https://www.readbyqxmd.com/read/27927912/gs-5759-a-bifunctional-%C3%AE-2-adrenoceptor-agonist-and-phosphodiesterase-4-inhibitor-for-chronic-obstructive-pulmonary-disease-with-a-unique-mode-of-action-effects-on-gene-expression-in-human-airway-epithelial-cells
#1
Taruna Joshi, Dong Yan, Omar Hamed, Stacey L Tannheimer, Gary B Phillips, Clifford D Wright, Musong Kim, Michael Salmon, Robert Newton, Mark A Giembycz
GS-5759 is a bifunctional ligand composed of a quinolinone-containing pharmacophore (β2A) found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to GSK 256066 by a pent-1-yn-1-ylbenzene spacer. GS-5759 had similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared to the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower...
December 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27923620/fluorescent-diphenylphosphonate-based-probes-for-detection-of-serine-protease-activity-during-inflammation
#2
Laura E Edgington-Mitchell, Nicholas Barlow, Luigi Aurelio, Aminath Samha, Monika Szabo, Bim Graham, Nigel Bunnett
Activity-based probes are small molecules that covalently bind to the active site of a protease in an activity-dependent manner. We synthesized and characterized two fluorescent activity-based probes that target serine proteases with trypsin-like or elastase-like activity. We assessed the selectivity and potency of these probes against recombinant enzymes and demonstrated that while they are efficacious at labeling active proteases in complex protein mixtures in vitro, they are less valuable for in vivo studies...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27920527/pharmacokinetics-and-safety-of-dts-108-a-human-oligopeptide-bound-to-sn-38-with-an-esterase-sensitive-cross-linker-in-patients-with-advanced-malignancies-a-phase-i-study
#3
Romain Coriat, Sandrine J Faivre, Olivier Mir, Chantal Dreyer, Stanislas Ropert, Mohammed Bouattour, Robert Desjardins, François Goldwasser, Eric Raymond
BACKGROUND: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage. METHODS: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1-2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/27918558/quantitating-drug-target-engagement-in-single-cells-in-vitro-and-in-vivo
#4
J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt, Labros G Meimetis, Claudio Vinegoni, Ralph Weissleder
Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target...
December 5, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#5
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27908755/synthesis-evaluation-and-molecular-modelling-studies-of-2-carbazol-3-yl-2-oxoacetamide-analogues-as-a-new-class-of-potential-pancreatic-lipase-inhibitors
#6
S N C Sridhar, George Ginson, P O Venkataramana Reddy, Mukund P Tantak, Dalip Kumar, Atish T Paul
A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition...
November 18, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908111/nuclear-quantum-effects-in-a-hiv-cancer-inhibitor-the-case-of-ellipticine
#7
Subrahmanyam Sappati, Ali Hassanali, Ralph Gebauer, Prasenjit Ghosh
Ellipticine is a natural product that is currently being actively investigated for its inhibitory cancer and HIV properties. Here we use path-integral molecular dynamics coupled with excited state calculations to characterize the role of nuclear quantum effects on the structural and electronic properties of ellipticine in water, a common biological solvent. Quantum effects collectively enhance the fluctuations of both light and heavy nuclei of the covalent and hydrogen bonds in ellipticine. In particular, for the ellipticine-water system, where the proton donor and acceptor have different proton affinities, we find that nuclear quantum effects (NQEs) strengthen both the strong and the weak H bonds...
November 28, 2016: Journal of Chemical Physics
https://www.readbyqxmd.com/read/27905163/fungal-glycolipid-hydrolase-inhibitors-and-their-effect-on-cryptococcus-neoformans
#8
Andres Gonzalez Santana, Christina Tysoe, Guanggan Hu, James Kronstad, Ethan Goddard-Borger, Stephen Withers
Pathogenic fungi kill an estimated 1.3 million people each year. This number is predicted to rise as drug resistance spreads, thus antifungal drugs with novel modes of action are urgently required. Fungal endoglycoceramidase-related proteins 1 and 2 (EGCrP-1 and -2), which hydrolyse glucosylceramide and ergosteryl beta-glucoside, respectively, are important for fungal cell growth and have been identified as potential targets for drug development. A library of iminosugar derivatives was screened against EGCrP-1 and -2, thereby identifying a number of competitive inhibitors with nanomolar affinities...
November 30, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27904766/the-role-of-pim1-in-the-ibrutinib-resistant-abc-subtype-of-diffuse-large-b-cell-lymphoma
#9
Hsu-Ping Kuo, Scott A Ezell, Sidney Hsieh, Karl J Schweighofer, Leo Wk Cheung, Shiquan Wu, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Yu Liang, Jeff Hsu, Chun-Te Chen, Darrin Beaupre, Betty Y Chang
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#10
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27902479/identification-of-a-novel-polo-like-kinase-1-inhibitor-that-specifically-blocks-the-functions-of-polo-box-domain
#11
Yunyu Chen, Jing Zhang, Dongsheng Li, Jiandong Jiang, Yanchang Wang, Shuyi Si
Polo-like kinase 1 (Plk1) is a promising target for cancer therapy due to its essential role in cell division. In addition to a highly conserved kinase domain, Plk1 also contains a Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. We adopted a fluorescence polarization assay and identified a new Plk1 PBD inhibitor T521 from a small-molecule compound library. T521 specifically inhibits the PBD of Plk1, but not those of Plk2-3. T521 exhibits covalent binding to some lysine residues of Plk1 PBD, which causes significant changes in the secondary structure of Plk1 PBD...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27898513/inhibition-of-plasmin-generation-in-plasma-by-heparin-low-molecular-weight-heparin-and-a-covalent-antithrombin-heparin-complex
#12
Gabriela M T Chang, Helen M Atkinson, Leslie R Berry, Anthony K C Chan
The clinical limitations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) led to the development of an antithrombin-heparin covalent complex (ATH), which displays superior anticoagulant abilities compared with UFH. A recent study investigating its interaction with fibrinolysis showed that ATH inhibited free and fibrin bound plasmin and decreased plasmin generation on fibrin clots. These studies were conducted using purified components and did not elucidate the interaction of ATH with plasmin in the presence of its natural inhibitors α2-antiplasmin (α2-AP) and α2-macroglobulin (α2-M)...
November 24, 2016: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
https://www.readbyqxmd.com/read/27898334/relative-contribution-of-ammonia-oxidizing-bacteria-and-other-members-of-nitrifying-activated-sludge-communities-to-micropollutant-biotransformation
#13
Yujie Men, Stefan Achermann, Damian E Helbling, David R Johnson, Kathrin Fenner
Improved micropollutant (MP) biotransformation during biological wastewater treatment has been associated with high ammonia oxidation activities, suggesting co-metabolic biotransformation by ammonia oxidizing bacteria as an underlying mechanism. The goal of this study was to clarify the contribution of ammonia oxidizing bacteria to increased MP degradation in nitrifying activated sludge (NAS) communities using a series of inhibition experiments. To this end, we treated a NAS community with two different ammonia oxidation inhibitors, namely octyne (OCT), a mechanistic inhibitor that covalently binds to ammonia monooxygenases, and allylthiourea (ATU), a copper chelator that depletes copper ions from the active center of ammonia monooxygenases...
November 22, 2016: Water Research
https://www.readbyqxmd.com/read/27890381/evaluation-of-dipeptide-nitriles-as-inhibitors-of-rhodesain-a-major-cysteine-protease-of-trypanosoma-brucei
#14
Tanja Schirmeister, Janina Schmitz, Sascha Jung, Torsten Schmenger, R Luise Krauth-Siegel, Michael Gütschow
A series of dipeptide nitriles known as inhibitors of mammalian cathepsins were evaluated for inhibition of rhodesain, the cathepsin L-like protease of Trypanosoma brucei. Compound 35 consisting of a Leu residue fitting into the S2 pocket and a triarylic moiety consisting of thiophene, a 1,2,4-oxadiazole and a phenyl ring fitting into the S3 pocket, and compound 33 with a 3-bromo-Phe residue (S2) and a biphenyl fragment (S3) were found to inhibit rhodesain in the single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27890005/mechanism-based-inhibitors-from-phytomedicine-risks-of-hepatotoxicity-and-their-potential-hepatotoxic-substructures
#15
Lili Wang, Xin He, Chunhuan Jin, Gregory Ondieki
The adverse reactions and side effects associated with use of herbal medicines, especially their damaging effects on the liver have increasingly been reported worldwide. Some of the herbal ingredients have the potential risk of herb-induced liver injury but their hepatotoxicity mechanisms and associated risk factors are not well characterized until now. Xenobiotics are catalyzed by cytochrome P450 enzymes into highly reactive metabolites, which can covalently bind to the enzyme itself and subsequently cause mechanism-based inhibition (MBI)...
November 23, 2016: Current Drug Metabolism
https://www.readbyqxmd.com/read/27886555/overcoming-multidrug-resistance-via-simultaneous-delivery-of-cytostatic-drug-and-p-glycoprotein-inhibitor-to-cancer-cells-by-hpma-copolymer-conjugate
#16
Ladislav Sivak, Vladimir Subr, Jakub Tomala, Blanka Rihova, Jiri Strohalm, Tomas Etrych, Marek Kovar
Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. MDR is either acquired as a result of previous repeated exposure to cytostatic drugs (P388/MDR cells) or naturally, as some tumors are congenitally resistant to chemotherapy (CT26 cells). One of the most common mechanisms of MDR is upregulation of P-glycoprotein (P-gp) expression. Here, we used HPMA copolymer conjugates, whereby the cytostatic drug doxorubicin (Dox) or the derivative of the P-gp inhibitor reversin 121 (R121) or both were covalently bound through a degradable pH-sensitive hydrazone bond...
January 2017: Biomaterials
https://www.readbyqxmd.com/read/27879666/structural-analysis-of-sortase-a-inhibitors
#17
Georgiana Nitulescu, Anca Zanfirescu, Octavian Tudorel Olaru, Isabela Madalina Nicorescu, George Mihai Nitulescu, Denisa Margina
Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors...
November 22, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27867011/tetrameric-acetyl-coa-acetyltransferase-1-is-important-for-tumor-growth
#18
Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun-Ying Lei, Yuancheng Li, Hui Mao, Benjamin H Lee, Jessica Sudderth, Ralph J DeBerardinis, Guojing Zhang, Taofeek Owonikoko, Manila Gaddh, Martha L Arellano, Hanna J Khoury, Fadlo R Khuri, Sumin Kang, Paul W Doetsch, Sagar Lonial, Titus J Boggon, Walter J Curran, Jing Chen
Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is "hijacked" to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27857147/molecular-mechanism-of-action-of-antimalarial-benzoisothiazolones-species-selective-inhibitors-of-the-plasmodium-spp-mep-pathway-enzyme-ispd
#19
Kathryn E Price, Christopher M Armstrong, Leah S Imlay, Dana M Hodge, C Pidathala, Natalie J Roberts, Jooyoung Park, Marwa Mikati, Raman Sharma, Alexandre S Lawrenson, Niraj H Tolia, Neil G Berry, Paul M O'Neill, Audrey R Odom John
The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P...
November 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27834131/recent-highlights-on-molecular-hybrids-potentially-useful-in-central-nervous-system-disorders
#20
Mariana Matias, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides, such as enkephalins, deltorphin and endomorphin, have been developed and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control...
November 11, 2016: Mini Reviews in Medicinal Chemistry
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