Discovery of novel irreversible inhibitors of IL-2 inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket

John D Harling, Angela M Deakin, Sébastien Campos, Rachel Grimley, Laiq Chaudry, Catherine Nye, Oxana Polyakova, Christina M Bessant, Nick Barton, Don Somers, John Barrett, Rebecca H Graves, Laura Hanns, W. J. Kerr, Roberto Solari

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

IL-2 inducible tyrosine kinase (Itk) plays a key role in antigen receptor signalling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted Cysteine442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by X-ray crystallography and enzymology, whilst demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models.
Original languageEnglish
Pages (from-to)28195-28206
Number of pages12
JournalJournal of Biological Chemistry
Issue number39
Early online date9 Aug 2013
DOIs
Publication statusPublished - 2013

Keywords

  • IL-2 inducible tyrosine kinase
  • Itk
  • tyrosine kinase
  • kinase inhibitor
  • novel irreversible inhibitors

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