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Covalent inhibitor

Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
Thomas Knoepfel, Pascal Furet, Robert Mah, Nicole Buschmann, Catherine Leblanc, Sebastien Ripoche, Diana Graus-Porta, Markus Wartmann, Inga Galuba, Robin A Fairhurst
As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity...
March 8, 2018: ACS Medicinal Chemistry Letters
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
Prithviraj Bose, Marina Y Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001-an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)-in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.
March 12, 2018: Cancer Cell
Yan Li, Zhenzhen Zhang, Wint Wint Phoo, Ying Ru Loh, Rong Li, Hai Yan Yang, Anna E Jansson, Jeffrey Hill, Thomas H Keller, Kassoum Nacro, Dahai Luo, CongBao Kang
Zika virus (ZIKV) infection has become a global public health concern. The viral NS2B-NS3 protease is an attractive antiviral target because of its role in maturation of viral non-structural proteins. Substrate-derived protease inhibitors have been investigated, but it remains challenging to develop them into drugs. Small-molecule inhibitors are of great interest in antiviral drug development. Here we report the structure and dynamics of ZIKV NS2B-NS3 protease covalently bound to a small-molecule inhibitor...
February 21, 2018: Structure
Kuppan Gokulan, Sangeeta Khare, Carl E Cerniglia, Steven L Foley, Kottayil I Varughese
The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross-linkages in bacterial cell walls. D,D-transpeptidase (D,D-TPs) generate the classical 4➔3 cross-linkages and the L,D-transpeptidase (L,D-TPs) generate the 3➔3 non-classical peptide cross-linkages...
March 9, 2018: AAPS Journal
Yuming Wang, Lijun Li, Jun Fan, Yang Dai, Alan Jiang, Mei-Yu Geng, Jing Ai, Wenhu Duan
Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2)...
March 9, 2018: Journal of Medicinal Chemistry
Mohammed Benadallah, Oualid Talhi, Fatiha Nouali, Nourredine Choukchou-Braham, Khaldoun Bachari, Artur M S Silva
The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the anti-hypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century...
March 9, 2018: Current Medicinal Chemistry
Kaja Bergant, Matej Janezic, Andrej Perdih
BACKGROUND: The family of DNA topoisomerases comprises a group of enzymes that catalyse the induction of topological changes to DNA. These enzymes play a role in the cell replication machinery and are, therefore, important targets for anticancer drugs - with human DNA topoisomerase IIα being one of the most prominent. Active compounds targeting this enzyme are classified into two groups with diverse mechanisms of action: DNA poisons act by stabilizing a covalent cleavage complex between DNA and the topoisomerase enzyme, transforming it into a cellular toxin, while the second diverse group of catalytic inhibitors, provides novel inhibition avenues for tackling this enzyme due to frequent occurrence of side effects observed during the DNA poison therapy...
March 6, 2018: Current Medicinal Chemistry
Jian Yang, Marta Barniol-Xicota, Minh T N Nguyen, Anezka Ticha, Kvido Strisovsky, Steven H L Verhelst
Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Tamara Maes, Cristina Mascaró, Iñigo Tirapu, Angels Estiarte, Filippo Ciceri, Serena Lunardi, Nathalie Guibourt, Alvaro Perdones, Michele M P Lufino, Tim C P Somervaille, Dan H Wiseman, Cihangir Duy, Ari Melnick, Christophe Willekens, Alberto Ortega, Marc Martinell, Nuria Valls, Guido Kurz, Matthew Fyfe, Julio Cesar Castro-Palomino, Carlos Buesa
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia...
February 23, 2018: Cancer Cell
Wenya Feng, Juan Qiao, Junfang Jiang, Bingbing Sun, Zhiwei Li, Li Qi
Alanine aminotransferase (ALT) plays significant role in biological and clinical research. In this study, a unique ALT enzyme reactor based on multifunctional polymer@magnetic nanoparticles has been constructed for the first time and the enzymolysis efficiency has been evaluated by chiral ligand exchange capillary electrophoresis technique. Poly(N-acryloxysuccinimide) has been synthesized by reversible addition-fragmentation chain transfer polymerization method and immobilized on the magnetic nanoparticles via the succinimide group in the polymer...
May 15, 2018: Talanta
Ameya D Bendre, Sureshkumar Ramasamy, C G Suresh
Legume Kunitz type trypsin inhibitor (KTI) family is one of the most versatile families of proteins. A typical KTI features a single peptide folded in β-trefoil manner, with the molecular weight about 20-22 kDa and two disulphide bonds. The members are known to inhibit a wide range of serpins proteases at the same time many of them possess unique features. Copaifera langsdorffii Trypsin inhibitor (CTI) has a β-trefoil fold made up of two non-covalently bound polypeptide chains with only a single disulfide bridge...
February 27, 2018: International Journal of Biological Macromolecules
Laura A McAllister, Christopher R Butler, Scot Mente, Steven V O'Neil, Kari R Fonseca, Justin R Piro, Julie A Cianfrogna, Timothy L Foley, Adam M Gilbert, Anthony R Harris, Christopher J Helal, Douglas S Johnson, Justin I Montgomery, Deane M Nason, Stephen Noell, Jayvardhan Pandit, Bruce N Rogers, Tarek A Samad, Christopher L Shaffer, Rafael Guimaraes da Silva, Daniel P Uccello, Damien Webb, Michael A Brodney
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway, and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group which confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups...
March 2, 2018: Journal of Medicinal Chemistry
Justin M Di Trani, Stephane De Cesco, Rebecca O'Leary, Jessica Plescia, Claudia Jorge do Nascimento, Nicolas Moitessier, Anthony K Mittermaier
Although drug development typically focuses on binding thermodynamics, recent studies suggest that kinetic properties can strongly impact a drug candidate's efficacy. Robust techniques for measuring inhibitor association and dissociation rates are therefore essential. To address this need, we have developed a pair of complementary isothermal titration calorimetry (ITC) techniques for measuring the kinetics of enzyme inhibition. The advantages of ITC over standard techniques include speed, generality, and versatility; ITC also measures the rate of catalysis directly, making it ideal for quantifying rapid, inhibitor-dependent changes in enzyme activity...
March 1, 2018: Nature Communications
Wojciech Stec, Kamila Rosiak, Cezary Treda, Maciej Smolarz, Joanna Peciak, Marcin Pacholczyk, Anna Lenart, Dawid Grzela, Ewelina Stoczynska-Fidelus, Piotr Rieske
Despite intensive research no therapies targeted against the oncogenic EGFRvIII are present in the clinic. One of the reasons is the elusive nature of the molecular structure and activity of the truncated receptor. The recent publications indicate the EGF-bound wild-type EGFR to trans -phosphorylate the EGFRvIII initiating aberrant signaling cascade. The elevated stability of the mutant receptor contributes towards oncogenic potential, preventing termination of signaling by receptor degradation. Here, we show that inhibition of phosphatases leads to a marked increase in phosphorylation of wild-type EGFR and EGFRvIII, indicating that both undergo cyclic rounds of phosphorylation and dephosphorylation on all investigated tyrosine residues, including Tyr1045...
February 2, 2018: Oncotarget
Joel A Rankin, Robert C Mauban, Matthias Fellner, Benoît Desguin, John McCracken, Jian Hu, Sergey A Varganov, Robert P Hausinger
Lactate racemase (LarA) of Lactobacillus plantarum contains a novel organometallic cofactor with nickel coordinated to a covalently-tethered pincer ligand, pyridinium-3-thioamide-5-thiocarboxylic acid mononucleotide, but its function in the enzyme mechanism has not been elucidated. This study presents direct evidence that the nickel-pincer cofactor facilitates a proton-coupled hydride transfer (PCHT) mechanism during LarA-catalyzed lactate racemization. No signal was detected by electron paramagnetic resonance spectroscopy for LarA in the absence or presence of substrate, consistent with a +2 metal oxidation state and inconsistent with a previously proposed proton-coupled electron transfer mechanism...
February 28, 2018: Biochemistry
Edward C Stites, Andrey S Shaw
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles...
February 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ann E Herman, Leslie W Chinn, Shweta G Kotwal, Elaine R Murray, Rui Zhao, Marilyn Florero, Alyse Lin, Anita Moein, Rena Wang, Meire Bremer, Serika Kokubu, Adrian P Serone, Eva L Hanze, Anders Viberg, Alyssa M Morimoto, Helen R Winter, Tamiko R Katsumoto
GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and non-covalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well-tolerated with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose [SAD] study; ≤250 mg twice daily [BID] and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study)...
February 27, 2018: Clinical Pharmacology and Therapeutics
Zhuo Liu, Luhong Wang, Min Feng, Yuanyuan Yi, Wenhan Zhang, Wenjuan Liu, Lei Li, Zhihao Liu, Yanxia Li, Xiaodong Ma
A new class of acrylamide-substituted quinazoline derivatives with enhanced inhibitory activity against mutant EGFR T790M enzyme were synthesized. Among them, compound 10b displayed the strongest inhibitory potency to block the phosphorylation of the EGFR T790M enzyme, with an IC50 value of 4.3 nM. Compared with the lead compound gefitinib, compound 10b significantly strengthened the activity against EGFR T790M (194 times higher). Furthermore, compound 10b only exhibited moderate activity against wild type EGFR, with an IC50 of 105...
February 15, 2018: Bioorganic Chemistry
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