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Current Medicinal Chemistry
ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
VOLUME: 17
ISSUE: 25
DOI: 10.2174/092986710791859333      Price:  $58









Non-ATP Competitive Protein Kinase Inhibitors

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Author(s): L. Garuti, M. Roberti and G. Bottegoni
Pages 2804-2821 (18)
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.
Keywords:
Allosteric, antitumor activity, inhibition, kinase, non-ATP competitive, SAR
Affiliation:
Department of Pharmaceutical Science, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.