Non-ATP Competitive Protein Kinase Inhibitors
| Autor: | Laura Garuti, Giovanni Bottegoni, Marinella Roberti |
|---|---|
| Přispěvatelé: | L. Garuti, M. Roberti, G. Bottegoni |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Stereochemistry Allosteric regulation Molecular Conformation Antineoplastic Agents Biochemistry Protein structure Drug Discovery Protein kinase A Protein Kinase Inhibitors Pharmacology chemistry.chemical_classification Molecular Structure biology Kinase Phosphotransferases Organic Chemistry Hydrogen Bonding MAP Kinase Kinase Kinases Small molecule Protein Structure Tertiary Enzyme chemistry Enzyme inhibitor Drug Design biology.protein Molecular Medicine Signal transduction Oligopeptides Protein Kinases |
| Zdroj: | Current Medicinal Chemistry. 17:2804-2821 |
| ISSN: | 0929-8673 |
| DOI: | 10.2174/092986710791859333 |
| Popis: | Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties. |
| Databáze: | OpenAIRE |
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