Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2
| Autor: | Brian C. Raimundo, Paul E. Boardman, Andrew Spencer, Kihang Choi, Guido Lanza, Cornelius Klöck, Xi Jin, Chaitan Khosla, John H. Griffin, Peter B. Madrid |
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| Rok vydání: | 2010 |
| Předmět: |
Indoles
Tissue transglutaminase Clinical Biochemistry Allosteric regulation Pharmaceutical Science Biochemistry Article Enzyme activator Inhibitory Concentration 50 Structure-Activity Relationship GTP-binding protein regulators Non-competitive inhibition GTP-Binding Proteins Drug Discovery Structure–activity relationship Humans Protein Glutamine gamma Glutamyltransferase 2 Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Transglutaminases biology Chemistry Organic Chemistry Enzyme Activation Enzyme Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 21(9) |
| ISSN: | 1464-3405 |
| Popis: | Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K(i) values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals. |
| Databáze: | OpenAIRE |
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