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Covalent inhibitor

Zaina T Al-Salama, Lesley J Scott
Lonoctocog alfa (rVIII-SingleChain; Afstyla(®)) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children...
September 12, 2017: Drugs
M Kavimani, V Balachandran, B Narayana, K Vanasundari, B Revathi
Experimental FT-IR and FT-Raman spectra of 2-methylphenylacetic acid (MPA) were recorded and theoretical values are also analyzed. The non-linear optical (NLO) properties were evaluated by determination of first (5.5053×10(-30) e.s.u.) and second hyper-polarizabilities (7.6833×10(-36) e.s.u.) of the title compound. The Multiwfn package is used to find the weak non-covalent interaction (Van der Wall interaction) and strong repulsion (steric effect) of the molecule and examined by reduced density gradient. The molecular electrostatic potential (MEP) analysis used to find the most reactive sites for the electrophilic and nucleophilic attack...
September 7, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
C D Andersson, N Martinez, D Zeller, S H Rondahl, M M Koza, B Frick, F Ekström, J Peters, A Linusson
An essential role of enzymes is to catalyze various chemical reactions in the human body and inhibition of the enzymatic activity by small molecules is the mechanism of action of many drugs or tool compounds used to study biological processes. Here, we investigate the effect on the dynamics of the serine protease α-chymotrypsin when in complex with two different covalently bound inhibitors using elastic incoherent neutron scattering. The results show that the inhibited enzyme displays enhanced dynamics compared to the free form...
September 12, 2017: Physical Chemistry Chemical Physics: PCCP
Imke H Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F Jones, Sergey Magnitsky, Ron J Keizer, Niels de Vries, Hilde Rosing, Nela Pawlowska, Scott Thomas, Mallika Dhawan, Rahul Aggarwal, Pamela N Munster, Laura J Esserman, Weiming Ruan, Alan H B Wu, Douglas Yee, Véronique Dartois, Radojka M Savic, Denise M Wolf, Laura van 't Veer
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice...
September 11, 2017: Breast Cancer Research: BCR
Michael Shokhen, Amnon Albeck
Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non-competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? Two fundamental features of rhomboid catalysis, the enzyme recognition and discrimination of substrates by TMD interactions in the exosite, and the concerted mechanism of non-covalent pre-catalytic complex to covalent tetrahedral complex (TC) conversion, provide answers to these mechanistic questions...
September 8, 2017: Protein Science: a Publication of the Protein Society
Kevin P Bohannon, Mary A Bittner, Daniel A Lawrence, Daniel Axelrod, Ronald W Holz
A lumenal secretory granule protein, tissue plasminogen activator (tPA), greatly slows fusion pore dilation and thereby slows its own discharge. We investigated another outcome of the long-lived narrow fusion pore: the creation of a nanoscale chemical reaction chamber for granule contents in which the pH is suddenly neutralized upon fusion. Bovine adrenal chromaffin cells endogenously express both tPA and its primary protein inhibitor, plasminogen activator inhibitor 1 (PAI). We found by immunocytochemistry that tPA and PAI are co-packaged in the same secretory granule...
September 7, 2017: Journal of General Physiology
Tjeerd Barf, Todd Covey, Raquel Izumi, Bas van de Kar, Michael Gulrajani, Bart van Lith, Maaike van Hoek, Edwin de Zwart, Diana Mittag, Dennis Demont, Saskia Verkaik, Fanny Krantz, Paul G Pearson, Roger Ulrich, Allard Kaptein
Several small-molecule BTK inhibitors are in development for B-cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib (1, ACP-196). Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential...
September 7, 2017: Journal of Pharmacology and Experimental Therapeutics
Xiao Zhou, Xiaoye Su, Pravin Pathak, Ryan Vik, Brittany Vinciguerra, Lyle Isaacs, Janarthanan Jayawickramarajah
Host-guest complexes are emerging as powerful components in functional systems with applications ranging from materials to biomedicine. In particular, CB7 based host-guest complexes have received much attention for the controlled release of drugs due to the remarkable ability of CB7 toward binding input molecules in water with high affinity leading to displacement of CB7 from included pharmacophores (or from drug loaded porous particles). However, the release of bound guests from CB7 in response to endogenous biological molecules remains limited since the input biomolecule needs to have the appropriate chemical structure to bind tightly into the CB7 cavity...
September 7, 2017: Journal of the American Chemical Society
Xiao-E Yan, Su-Jie Zhu, Ling Liang, Peng Zhao, Hwan Geun Choi, Cai-Hong Yun
Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs...
August 8, 2017: Oncotarget
Lars Dittus, Thilo Werner, Marcel Muelbaier, Marcus Bantscheff
Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the comprehensive assessment of inhibitor selectivity for covalent and noncovalent targets...
September 12, 2017: ACS Chemical Biology
Karina Calvopiña, Philip Hinchliffe, Jürgen Brem, Kate J Heesom, Samar Johnson, Ricky Cain, Christopher T Lohans, Colin W G Fishwick, Christopher J Schofield, James Spencer, Matthew B Avison
Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine...
September 6, 2017: Molecular Microbiology
Nikolaos D Georgakopoulos, Michele Frison, Maria Soledad Alvarez, Hélène Bertrand, Geoff Wells, Michelangelo Campanella
Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1...
September 4, 2017: Scientific Reports
Abdullah Akbar, Nicole M R McNeil, Marie R Albert, Viviane Ta, Gautam Adhikary, Karine Bourgeois, Richard L Eckert, Jeffrey W Keillor
Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold...
September 14, 2017: Journal of Medicinal Chemistry
Julian Engel, Steven Smith, Jonas Lategahn, Hannah L Tumbrink, Lisa Goebel, Christian Becker, Elisabeth Hennes, Marina Keul, Anke Unger, Heiko Müller, Matthias Baumann, Carsten Schultz-Fademrecht, Georgia Günther, Jan G Hengstler, Daniel Rauh
Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance...
September 18, 2017: Journal of Medicinal Chemistry
Jonathan Pettinger, Keith Jones, Matthew David Cheeseman
Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small molecule/protein crystal structures to design tight-binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ε-amino group in lysine, this strategy generates a number of specific challenges...
August 29, 2017: Angewandte Chemie
Nicholas J Porter, David W Christianson
Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the α,β-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 Å resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis...
September 15, 2017: ACS Chemical Biology
Michael Forster, Matthias Gehringer, Stefan A Laufer
Janus kinases (JAKs) are a family of four cytosolic protein kinases with a high degree of structural similarity. Due to its very restricted role in immune regulation, JAK3 was promoted as an excellent target for immunosuppression for more than a decade, but clinical validation of this concept is still elusive. During the last years, speculation arose that kinase activity of JAK1, which cooperates with JAK3 in cytokine receptor signaling, may have a dominant role over the one of JAK3. Until recently, however, this issue could not be appropriately addressed due to a lack of highly isoform-selective tool compounds...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
Adam B Shapiro, Ning Gao, Haris Jahić, Nicole M Carter, April Chen, Alita A Miller
ETX2514 is a non-β-lactam serine β-lactamase inhibitor in clinical development that has greater potency and broader spectrum of β-lactamase inhibition than the related diazabicyclooctanone avibactam. Despite opening of its cyclic urea ring upon acylation, avibactam can recyclize and dissociate intact from certain β-lactamases. We investigated reversibility of ETX2514 acylation of 10 serine β-lactamases representing Ambler classes A, C, and D. Dissociation rate constants varied widely between enzymes and were lowest for class D...
August 28, 2017: ACS Infectious Diseases
Aarfa Queen, Parvez Khan, Danish Idrees, Amir Azam, Md Imtaiyaz Hassan
To find potential inhibitors of human carbonic anhydrase IX (CAIX), we have successfully deigned, synthesized and characterized three p-Toluene sulphonylhydrazone derivatives (1-3). Molecular docking studies provided the structural basis of CAIX inhibition and a deeper insight into the protein-ligand interactions. p-Toluene sulphonylhydrazone derivatives show a well organized conformational compatibility with the active site of CAIX. This protein-ligand complex was stabilized by several non-covalent interactions offered by residues present in the active site cavity...
August 19, 2017: International Journal of Biological Macromolecules
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