Non-ATP competitive protein kinase inhibitors

L. Garuti*, M. Roberti, G. Bottegoni

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

Abstract

Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATPcompetitive 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 IC50smeasured 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.

Original languageEnglish
Pages (from-to)2804-2821
Number of pages18
JournalCurrent medicinal chemistry
Volume17
Issue number25
DOIs
Publication statusPublished - 20 Aug 2010
Externally publishedYes

Keywords

  • Allosteric
  • Antitumor activity
  • Inhibition
  • Kinase
  • Non-atp competitive
  • Sar

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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