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Covalent inhibitor

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https://www.readbyqxmd.com/read/28230989/development-of-the-first-generation-of-disulfide-based-subtype-selective-and-potent-covalent-pyruvate-dehydrogenase-kinase-1-pdk1-inhibitors
#1
Yifu Liu, Zuoquan Xie, Dan Zhao, Jin Zhu, Fei Mao, Shuai Tang, Hui Xu, Cheng Luo, Mei-Yu Geng, Min Huang, Jian Li
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described Bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, based on the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analog, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17×103M-1s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28228478/an-engineered-tgf-%C3%AE-monomer-that-functions-as-a-dominant-negative-to-block-tgf-%C3%AE-signaling
#2
Sun Kyung Kim, Lindsey Barron, Cynthia S Hinck, Elyse M Petrunak, Kristin E Cano, Avinash Thangirala, Brian Iskra, Molly Brothers, Machell Vonberg, Belinda Leal, Blair Richter, Ravindra Kodali, Alex B Taylor, Shoucheng Du, Christopher O Barnes, Traian Sulea, Guillermo Calero, P John Hart, Matthew J Hart, Borries Demeler, Andrew P Hinck
The transforming growth factor beta isoforms, TGF-β1, -β2, and -β3 are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor, TβRI, but dispensible for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor, TβRII, as an alternative therapeutic modality for blocking TGF-β signaling in humans...
February 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28225269/indazole-based-covalent-inhibitors-to-target-drug-resistant-epidermal-growth-factor-receptor
#3
Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah Lea Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel Rauh
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds...
February 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28225177/an-irreversible-inhibitor-of-hsp72-that-unexpectedly-targets-lysine-56
#4
Jonathan Pettinger, Yann-Vaï Le Bihan, Marcella Widya, Rob L M van Montfort, Keith Jones, Matthew D Cheeseman
The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition...
February 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28196299/activity-based-probes-for-the-ubiquitin-conjugation-deconjugation-machinery-new-chemistries-new-tools-and-new-insights
#5
REVIEW
David S Hewings, John A Flygare, Matthew Bogyo, Ingrid E Wertz
The reversible post-translational modification of proteins by ubiquitin and ubiquitin-like proteins regulates almost all cellular processes, by affecting protein degradation, localization, and complex formation. Deubiquitinases (DUBs) are proteases that remove ubiquitin modifications or cleave ubiquitin chains. Most DUBs are cysteine proteases, which makes them well suited for study by activity-based probes. These DUB probes report on deubiquitinase activity by reacting covalently with the active site in an enzyme-catalyzed manner...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28193034/leveraging-gas-phase-fragmentation-pathways-for-improved-identification-and-selective-detection-of-targets-modified-by-covalent-probes
#6
Scott B Ficarro, Christopher M Browne, Joseph D Card, William M Alexander, Tinghu Zhang, Eunyoung Park, Randall McNally, Sirano Dhe-Paganon, Hyuk-Soo Seo, Ilaria Lamberto, Michael J Eck, Sara J Buhrlage, Nathanael S Gray, Jarrod A Marto
The recent approval of covalent inhibitors for multiple clinical indications has reignited enthusiasm for this class of drugs. As interest in covalent drugs has increased, so too has the need for analytical platforms that can leverage their mechanism-of-action to characterize modified protein targets. Here we describe novel gas phase dissociation pathways which yield predictable fragment ions during MS/MS of inhibitor-modified peptides. We find that these dissociation pathways are common to numerous cysteine-directed probes as well as the covalent drugs, Ibrutinib and Neratinib...
December 20, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#7
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28183185/rational-design-of-selective-and-bioactive-inhibitors-of-the-mycobacterium-tuberculosis-proteasome
#8
Kyle A Totaro, Dominik Barthelme, Peter T Simpson, Xiuju Jiang, Gang Lin, Carl F Nathan, Robert T Sauer, Jason K Sello
The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28183184/a-small-covalent-allosteric-inhibitor-of-human-cytomegalovirus-dna-polymerase-subunit-interactions
#9
Han Chen, Molly Coseno, Scott B Ficarro, My Sam Mansueto, Gloria Komazin-Meredith, Sandrine Boissel, David J Filman, Jarrod A Marto, James M Hogle, Donald M Coen
Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28179993/close-encounter-of-the-covalent-kind-inhibiting-mcl1-s-proapoptotic-activity-with-covalent-inhibitors
#10
EDITORIAL
Guillaune Lessene
No abstract text is available yet for this article.
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28166608/safety-efficacy-and-pharmacokinetics-of-rviii-singlechain-in-children-with-severe-hemophilia-a-sesults-of-a-multicenter-clinical-trial
#11
Oleksandra Stasyshyn, Claudia Djambas Khayat, Genadi Iosava, Jeannie Ong, Faraizah Abdul Karim, Kathelijn Fischer, Alex Veldman, Nicole Blackman, Katie St Ledger, Ingrid Pabinger
BACKGROUND: rVIII-SingleChain, is a novel B-domain truncated recombinant Factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand Factor. OBJECTIVES: This Phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients <12 years of age with severe hemophilia A. PATIENTS/METHODS: Patients could be assigned to prophylaxis or on-demand therapy by the investigator...
February 6, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28165718/modification-of-the-orthosteric-ppar%C3%AE-covalent-antagonist-scaffold-yields-an-improved-dual-site-allosteric-inhibitor
#12
Richard Brust, Hua Lin, Jakob Fuhrmann, Alice Asteian, Theodore M Kamenecka, Douglas J Kojetin
GW9662 and T0070907 are widely used commercially available irreversible antagonists of peroxisome proliferator-activated receptor gamma (PPARγ). These antagonists covalently modify Cys285 located in an orthosteric ligand-binding pocket embedded in the PPARγ ligand-binding domain and are used to block binding of other ligands. However, we recently identified an alternate/allosteric ligand-binding site in the PPARγ LBD to which ligand binding is not inhibited by these orthosteric covalent antagonists. Here, we developed a series of analogs based on the orthosteric covalent antagonist scaffold with the goal of inhibiting both orthosteric and allosteric cellular activation of PPARγ by MRL20, an orthosteric agonist that also binds to an allosteric site...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28164761/mitogen-activated-protein-kinase-mapk-interacting-kinases-1-and-2-mnk1-and-mnk2-as-targets-for-cancer-therapy-recent-progress-in-the-development-of-mnk-inhibitors
#13
Agnieszka Dreas, Maciej Mikulski, Mariusz Milik, Charles-Henry Fabritius, Krzysztof Brzózka, Tomasz Rzymski
BACKGROUND: MNK1 and MNK2 are MAP kinase-interacting serine/threonine kinases, which are activated by RAS and MAPK signaling pathways and are involved in regulation of protein translation. Both kinases phosphorylate translation initiation factor eIF4E on a conserved serine 209. Overactivated eIF4E can act as an oncogene and contribute to the transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, knockout mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype...
February 3, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28162105/molecular-insights-into-cancer-therapeutic-effects-of-the-dietary-medicinal-phytochemical-withaferin-a
#14
Chandra Sekhar Chirumamilla, Claudina Pérez-Novo, Xaveer Van Ostade, Wim Vanden Berghe
Despite the worldwide research efforts to combat cancer, it remains a leading cause of death. Although various specific kinase inhibitors already have been approved for clinical cancer treatment, occurrence of intrinsic or acquired resistance and intermittent response over longer periods limits long-term success of single kinase-targeted therapies. In this respect, there is a renewed interest in polypharmaceutical natural compounds, which simultaneously target various hyperactivated kinases involved in tumour-inflammation, angiogenesis, cell survival, proliferation, metastasis and angiogenesis...
February 6, 2017: Proceedings of the Nutrition Society
https://www.readbyqxmd.com/read/28160417/nmr-structure-based-optimization-of-staphylococcus-aureus-sortase-a-pyridazinone-inhibitors
#15
Albert H Chan, Sung Wook Yi, Ethan M Weiner, Brendan R Amer, Christopher K Sue, Jeff Wereszczynski, Carly A Dillen, Silvia Senese, Jorge Z Torres, J Andrew McCammon, Lloyd S Miller, Michael E Jung, Robert T Clubb
Staphylococcus aureus is a leading cause of hospital-acquired infections in the United States and is a major health concern as methicillin-resistant S. aureus (MRSA) and other antibiotic resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches...
February 3, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28157311/structure-based-library-design-and-fragment-screening-for-the-identification-of-reversible-complement-factor-d-protease-inhibitors
#16
Anna Vulpetti, Stefan Randl, Simon Rüdisser, Nils Ostermann, Paul Erbel, Aengus Mac Sweeney, Thomas Zoller, Bahaa Salem, Bernd Gerhartz, Frederic Cumin, Ulrich Hommel, Claudio Dalvit, Edwige Lorthiois, Jürgen Maibaum
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries...
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28153250/fabrication-of-enzyme-reactor-utilizing-magnetic-porous-polymer-membrane-for-screening-d-amino-acid-oxidase-inhibitors
#17
Jun Fang Jiang, Juan Qiao, Xiao Yu Mu, Myeong Hee Moon, Li Qi
In this work, a unique D-amino acid oxidase reactor for enhanced enzymolysis efficiency is presented. A kind of magnetic polymer matrices, composed of iron oxide nanoparticles and porous polymer membrane (poly styrene-co-maleic anhydride), was prepared. With covalent bonding D-Amino acid oxidase on the surface of the matrices and characterization of scanning electron microscope and vibrating sample magnetometer, it demonstrated that the membrane enzyme reactor was successfully constructed. The enzymolysis efficiency of the enzyme reactor was evaluated and the apparent Michaelis-Menten constants of D-Amino acid oxidase were determined (Km was 1...
April 1, 2017: Talanta
https://www.readbyqxmd.com/read/28152568/apolipoprotein-a-inhibits-hepatitis-c-virus-entry-through-interaction-with-infectious-particles
#18
Catarina Oliveira, Carole Fournier, Véronique Descamps, Virginie Morel, Corey A Scipione, Rocco Romagnuolo, Marlys L Koschinsky, Agnès Boullier, Paulo Marcelo, Jean-Marc Domon, Etienne Brochot, Gilles Duverlie, Catherine Francois, Sandrine Castelain, Francois Helle
: The development of different cell culture models has greatly contributed to improve the knowledge of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. This would open new perspectives to study HCV biology, including drug resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient and size-exclusion chromatography, we obtained a purified fraction enriched in inhibitory factors from HCV seronegative sera...
February 2, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28150528/theoretical-studies-on-the-interaction-between-the-nitrile-based-inhibitors-and-the-catalytic-triad-of-cathepsin-k
#19
C Pitchumani Violet Mary, R Shankar, S Vijayakumar
Computational studies on the interaction of novel inhibitor compounds with the Cathepsin K protease has been performed to study the inhibition properties of the inhibitor compounds. The quantum chemical calculations have been performed to analyze the molecular geometries, structural stability, reactivity, nature of interaction and the charge transfer properties using B3LYP level of theory by implementing 6-311g(d,p) basis set. The calculated C-S and N-H...N bond lengths of the inhibitor-triad complexes are found to agree well with the previous literature results...
February 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28149532/bivalent-iap-antagonists-but-not-monovalent-iap-antagonists-inhibit-tnf-mediated-nf-%C3%AE%C2%BAb-signaling-by-degrading-traf2-associated-ciap1-in-cancer-cells
#20
Y Mitsuuchi, C A Benetatos, Y Deng, T Haimowitz, S C Beck, M R Arnone, G S Kapoor, M E Seipel, S K Chunduru, M A McKinlay, C G Begley, S M Condon
The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates...
2017: Cell Death Discovery
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