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J Biol Chem. 2013 Sep 27;288(39):28195-206. doi: 10.1074/jbc.M113.474114. Epub 2013 Aug 9.

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

Author information

1
From the Allergic Inflammation Discovery Performance Unit and.

Abstract

IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling 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 cysteine 442 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 while 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.

KEYWORDS:

Asthma; Drug Discovery; IL-2-inducible Tyrosine Kinase; Kinase Inhibitor; Medicinal Chemistry; Nonreceptor Tyrosine Kinase; T Cell

PMID:
23935099
PMCID:
PMC3784729
DOI:
10.1074/jbc.M113.474114
[Indexed for MEDLINE]
Free PMC Article

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