scholarly journals Covalent Aurora A regulation by the metabolic integrator coenzyme A

2018 ◽  
Author(s):  
Yugo Tsuchiya ◽  
Dominic P Byrne ◽  
Selena G Burgess ◽  
Jenny Bormann ◽  
Jovana Bakovic ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Coenzyme A ◽  
Covalent Bond ◽  
Aurora A ◽  
Cell Cycle Protein ◽  
Covalent Interaction ◽  
Oxidative Stresses ◽  
Cellular Analysis ◽  
Activation Segment ◽  
Reversible Covalent

SummaryAurora A is a cell cycle protein kinase implicated in multiple human cancers, and several Aurora A-specific kinase inhibitors have progressed into clinical trials. In this study, we report structural and cellular analysis of a novel biochemical mode of Aurora A inhibition, which occurs through reversible covalent interaction with the universal metabolic integrator coenzyme A (CoA). Mechanistically, the CoA 3’-phospho ADP moiety interacts with Thr 217, an Aurora A selectivity filter, which permits the formation of an unprecedented covalent bond with Cys 290 in the kinase activation segment, lying some 15 Å away. CoA modification (CoAlation) of endogenous Aurora A is rapidly induced by oxidative stresses at Cys 290 in human cells, and microinjection of CoA into mouse embryos perturbs meitoic spindle formation and chromosome alignment. Aurora A regulation by CoA reveals how targeting of Aurora A might be accomplished in the future by development of a ‘double-anchored’ covalent inhibitor.

Synthesis and tubulin interaction of thiocolchicines containing an isothiocyanato group. Synthesis of C(2)-deuterated and C(2)-14C-labeled 7-isothiocyanatodeacetamidothiocolchicine

1991 ◽  
Vol 56 (11) ◽  
pp. 2306-2312 ◽  
Author(s):  
Anjum Muzaffar ◽  
Ernest Hamel ◽  
Rouli Bai ◽  
Arnold Brossi
Keyword(s):  
Binding Site ◽  
Covalent Bond ◽  
Tubulin Polymerization ◽  
Low Concentration ◽  
Covalent Interaction ◽  
Isotope Label ◽  
Colchicine Binding Site

Synthesis of isothiocyanato substituted thiocolchicines XI - XIV is described. Introduction of an isotope label is demonstrated with the deuterated isothiocyanate XII and the 14C-labeled analog XIII. These isothiocyanates inhibit tubulin polymerization at low concentration. In addition, the 14C-labeled XIII forms covalent bond(s) with tubulin. Unfortunately, the covalent reaction while rapid, is not inhibited by preincubation of tubulin with colchicine. The covalent interaction of XIII with tubulin thus appears to be nonspecific, limiting its use as a marker of the colchicine binding site on tubulin.

scholarly journals Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1103
Author(s):  
Philipp von Hundelshausen ◽  
Wolfgang Siess
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Phase 1 ◽  
The Novel ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Dermatological Disorders ◽  
Reversible Covalent

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

scholarly journals Molecular recognition of organic ammonium ions in solution using synthetic receptors

2010 ◽  
Vol 6 ◽  
Author(s):  
Andreas Späth ◽  
Burkhard König
Keyword(s):  
Molecular Recognition ◽  
Hydrophobic Interactions ◽  
Covalent Bond ◽  
Ammonium Ion ◽  
Synthetic Receptors ◽  
Ammonium Ions ◽  
Wide Range ◽  
Covalent Bond Formation ◽  
Reversible Covalent ◽  
Ion Receptors

Ammonium ions are ubiquitous in chemistry and molecular biology. Considerable efforts have been undertaken to develop synthetic receptors for their selective molecular recognition. The type of host compounds for organic ammonium ion binding span a wide range from crown ethers to calixarenes to metal complexes. Typical intermolecular interactions are hydrogen bonds, electrostatic and cation–π interactions, hydrophobic interactions or reversible covalent bond formation. In this review we discuss the different classes of synthetic receptors for organic ammonium ion recognition and illustrate the scope and limitations of each class with selected examples from the recent literature. The molecular recognition of ammonium ions in amino acids is included and the enantioselective binding of chiral ammonium ions by synthetic receptors is also covered. In our conclusion we compare the strengths and weaknesses of the different types of ammonium ion receptors which may help to select the best approach for specific applications.

Benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one derivatives as Aurora A kinase inhibitors: LQTA-QSAR analysis and detailed systematic validation of the developed model

2015 ◽  
Vol 19 (4) ◽  
pp. 965-974 ◽  
Author(s):  
Ashish M. Kanhed ◽  
Radha Charan Dash ◽  
Nishant Parmar ◽  
Tarun Kumar Das ◽  
Rajani Giridhar ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Qsar Analysis

ChemInform Abstract: Single Step Synthesis of New Fused Pyrimidine Derivatives and Their Evaluation as Potent Aurora-A Kinase Inhibitors.

ChemInform ◽  
2011 ◽  
Vol 43 (4) ◽  
pp. no-no
Author(s):  
Mohamed R. Shaaban ◽  
Tamer S. Saleh ◽  
Abdelrahman S. Mayhoub ◽  
Ahmad M. Farag
Keyword(s):  
Kinase Inhibitors ◽  
Single Step ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Pyrimidine Derivatives
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