Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket |
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Authors: | 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 William J Kerr Roberto Solari |
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Institution: | From the ‡Allergic Inflammation Discovery Performance Unit and ;§Platform Technology Sciences, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom and ;the ¶Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom |
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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. |
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Keywords: | Asthma Drug Discovery Medicinal Chemistry Nonreceptor Tyrosine Kinase T Cell IL-2-inducible Tyrosine Kinase Kinase Inhibitor |
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