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Covalent inhibitor

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https://www.readbyqxmd.com/read/28646426/eftrenonacog-alfa-a-review-in-haemophilia-b
#1
Sheridan M Hoy
Eftrenonacog alfa (Alprolix™) is a recombinant fusion protein comprising human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 (i.e. rFIXFc). The presence of the Fc domain extends the terminal half-life (t½) of rFIXFc, permitting prolonged treatment intervals. rFIXFc is available for intravenous use for the prophylaxis and treatment of bleeding in patients with haemophilia B. In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, rFIXFc prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens...
June 23, 2017: Drugs
https://www.readbyqxmd.com/read/28637898/activation-of-complement-by-pigment-epithelium-derived-factor-in-rheumatoid-arthritis
#2
Leonie M Vogt, Simone Talens, Ewa Kwasniewicz, Carsten Scavenius, André Struglics, Jan J Enghild, Tore Saxne, Anna M Blom
The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family...
June 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#3
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28631349/tuning-sulfur-oxidation-states-on-thioether-bridged-peptide-macrocycles-for-modulation-of-protein-interactions
#4
Gabriella Perell, Rachel Staebell, Mehrdad Hairani, Alessandro Cembran, William Charles Krause Pomerantz
Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in non-covalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein-protein interaction (PPI) inhibitors. Here we use a model PPI between -helical MLL and KIX to evaluate oxidation effects on sulfur-containing macrocycle structure, stability, and protein affinity. Desolvation effects from varied polarity states were evaluated computationally and experimentally at the side chain, amino acid and peptide level...
June 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28630679/molecular-interactions-of-amyloid-nanofibrils-with-biological-aggregation-modifiers-implications-for-cytotoxicity-mechanisms-and-biomaterial-design
#5
REVIEW
Durga Dharmadana, Nicholas P Reynolds, Charlotte E Conn, Céline Valéry
Amyloid nanofibrils are ubiquitous biological protein fibrous aggregates, with a wide range of either toxic or beneficial activities that are relevant to human disease and normal biology. Protein amyloid fibrillization occurs via nucleated polymerization, through non-covalent interactions. As such, protein nanofibril formation is based on a complex interplay between kinetic and thermodynamic factors. The process entails metastable oligomeric species and a highly thermodynamically favoured end state. The kinetics, and the reaction pathway itself, can be influenced by third party moieties, either molecules or surfaces...
August 6, 2017: Interface Focus
https://www.readbyqxmd.com/read/28628261/studying-the-conformation-of-a-receptor-tyrosine-kinase-in-solution-by-inhibitor-based-spin-labeling
#6
Dongsheng M Yin, Jeffrey S Hannam, Anton Schmitz, Olav Schiemann, Gregor Hagelueken, Michael Famulok
The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR...
June 19, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28626547/structure-guided-optimization-of-quinoline-inhibitors-of-plasmodium-n-myristoyltransferase
#7
Victor Goncalves, James A Brannigan, Alice Laporte, Andrew S Bell, Shirley M Roberts, Anthony J Wilkinson, Robin J Leatherbarrow, Edward W Tate
The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-Myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT).
January 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28623374/nucleotide-based-covalent-inhibitors-of-kras-can-only-be-efficient-in-vivo-if-they-bind-reversibly-with-gtp-like-affinity
#8
Matthias P Müller, Sadasivam Jeganathan, Angelika Heidrich, Jeremy Campos, Roger S Goody
Simple reversible competitive inhibition of nucleotide binding of GTP to Ras family GTPases has long been recognized as an unlikely approach to manipulating the activity of such proteins for experimental or therapeutic purposes. This is due to the high affinity of GTP to GTPases coupled with high cellular GTP concentrations, but also to problems of specificity for the highly conserved binding sites in GTPases. A recent approach suggested that these problems might be overcome by using GDP derivatives that can undergo a covalent reaction with disease specific mutants, in particular addressing inhibition of KRasG12C using GDP equipped with an electrophilic group at the β-phosphate...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28621541/expanding-the-scope-of-electrophiles-capable-of-targeting-k-ras-oncogenes
#9
Lynn M McGregor, Meredith L Jenkins, Caitlin Kerwin, John E Burke, Kevan M Shokat
There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28621538/discovery-of-highly-potent-and-selective-small-molecule-reversible-factor-d-inhibitors-demonstrating-alternative-complement-pathway-inhibition-in-vivo
#10
Edwige Lorthiois, Karen Anderson, Anna Vulpetti, Olivier Rogel, Frederic Cumin, Nils Ostermann, Stefan Steinbacher, Aengus Mac Sweeney, Omar Delgado, Sha-Mei Liao, Stefan Randl, Simon Rüdisser, Solene Dussauge, Kamal Fettis, Laurence Kieffer, Andrea de Ekernez, Louis Yang, Constanze Hartwieg, Upendra A Argikar, Laura R LaBonte, Ronald Newton, Viral Kansara, Stefanie Flohr, Ulrich Hommel, Bruce Jaffee, Jürgen Maibaum
The highly specific S1 serine protease Factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of non-covalent reversible and selective human Factor D (FD) inhibitors with drug-like properties...
June 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28613814/2-chloropropionamide-as-a-low-reactivity-electrophile-for-irreversible-small-molecule-probe-identification
#11
Dharmaraja Allimuthu, Drew J Adams
Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28609675/covalent-inhibitors-an-opportunity-for-rational-target-selectivity
#12
REVIEW
Roman Lagoutte, Remi Patouret, Nicolas Winssinger
There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors...
June 10, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28605587/allosteric-regulation-of-phosphatidylinositol-4-kinase-iii-beta-by-an-anti-picornavirus-compound-mdl-860
#13
Minetaro Arita, Georgi Dobrikov, Gerhard Pürstinger, Angel Galabov
MDL-860 is a broad-spectrum anti-picornavirus compound discovered in 1982, and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized anti-poliovirus activity of MDL-860, and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860...
June 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28603991/trisubstituted-pyridinylimidazoles-as-potent-inhibitors-of-the-clinically-resistant-l858r-t790m-c797s-egfr-mutant-targeting-of-both-hydrophobic-regions-and-the-phosphate-binding-site
#14
Marcel Günther, Jonas Lategahn, Michael Juchum, Eva Döring, Marina Keul, Julian Engel, Hannah L Tumbrink, Daniel Rauh, Stefan Laufer
Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28602917/crystal-structure-of-mutant-form-cys115his-of-citrobacter-freundii-methionine-%C3%AE-lyase-complexed-with-l-norleucine
#15
Svetlana V Revtovich, Elena A Morozova, Vitalia V Kulikova, Natalya V Anufrieva, Tatyana I Osipova, Vasiliy S Koval, Alexey D Nikulin, Tatyana V Demidkina
The mutant form of Citrobacter freundii methionine γ-lyase with the replacement of active site Cys115 for His has been found to be inactive in the γ-elimination reaction of methionine while fully active in the γ-elimination reaction of O-acetyl-l-homoserine and in the β-elimination reaction of S-alk(en)yl-substituted cysteines. In this work, the crystal structure of the mutant enzyme complexed with competitive inhibitor, l-norleucine was determined at 1.45Å resolution. At the enzyme active site the inhibitor proved to be bound both noncovalently and covalently, which corresponds to the two intermediates of the γ- and β-elimination reactions, Michaelis complex and the external aldimine...
June 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28600847/the-fifth-subunit-of-the-%C3%AE-4%C3%AE-2-2-%C3%AE-2-nicotinic-acetylcholine-receptor-modulates-maximal-ach-responses
#16
Karina New, Silvia Garcia Del Villar, Simone Mazzaferro, Constanza Alcaino, Isabel Bermudez
BACKGROUND AND PURPOSE: The fifth subunit in the (α4β2)2 α4 nicotinic acetylcholine receptor (nAChR) plays a determining role in the pharmacology of this nAChR type. Here, we have examined the role of the fifth subunit in the ACh responses of the (α4β2)2 β2 nAChR type. EXPERIMENTAL APPROACH: The role of the fifth subunit in receptor function was explored using two-electrode voltage-clamp electrophysiology, along with subunit-targeted mutagenesis and the substituted cysteine scanning method applied to fully linked (α4β2)2 β2 receptors...
June 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28598431/a-covalent-pin1-inhibitor-selectively-targets-cancer-cells-by-a-dual-mechanism-of-action
#17
Elena Campaner, Alessandra Rustighi, Alessandro Zannini, Alberto Cristiani, Silvano Piazza, Yari Ciani, Ori Kalid, Gali Golan, Erkan Baloglu, Sharon Shacham, Barbara Valsasina, Ulisse Cucchi, Agnese Chiara Pippione, Marco Lucio Lolli, Barbara Giabbai, Paola Storici, Paolo Carloni, Giulia Rossetti, Federica Benvenuti, Ezia Bello, Maurizio D'Incalci, Elisa Cappuzzello, Antonio Rosato, Giannino Del Sal
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs...
June 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28588484/akrinor-tm-a-cafedrine-theodrenaline-mixture-20-1-increases-force-of-contraction-of-human-atrial-myocardium-but-does-not-constrict-internal-mammary-artery-in-vitro
#18
Benjamin Kloth, Simon Pecha, Eileen Moritz, Yvonne Schneeberger, Klaus-Dieter Söhren, Edzard Schwedhelm, Hermann Reichenspurner, Thomas Eschenhagen, Rainer H Böger, Torsten Christ, Sebastian N Stehr
Background: Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor(TM) consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of Akrinor(TM) and its constituents on contractile force and tension in human atrial trabeculae and internal A...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28578874/dissecting-the-specificity-of-adenosyl-sulfamate-inhibitors-targeting-the-ubiquitin-activating-enzyme
#19
Mohit Misra, Maximilian Kuhn, Mark Löbel, Heeseon An, Alexander V Statsyuk, Christoph Sotriffer, Hermann Schindelin
Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site...
May 26, 2017: Structure
https://www.readbyqxmd.com/read/28577368/inhibitors-of-ubiquitin-e3-ligase-as-potential-new-antimalarial-drug-leads
#20
Jagrati Jain, Surendra K Jain, Larry A Walker, Babu L Tekwani
BACKGROUND: Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes...
June 2, 2017: BMC Pharmacology & Toxicology
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