title: Non-ATP competitive protein kinase inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Science, University of Bologna, Italy. laura.garuti@unibo.it
authors.forename: L
authors.initials: L
authors.lastname: Garuti
authors.forename: M
authors.initials: M
authors.lastname: Roberti
authors.forename: G
authors.initials: G
authors.lastname: Bottegoni
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006860:Hydrogen Bonding; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism; D010770:Phosphotransferases / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases; D017434:Protein Structure, Tertiary
chemical_list: D000970:Antineoplastic Agents; C553185:DFG peptide; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases; D011494:Protein Kinases; D020930:MAP Kinase Kinase Kinases