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

Harling, John D and Deakin, Angela M and Campos, Sébastien and Grimley, Rachel and Chaudry, Laiq and Nye, Catherine and Polyakova, Oxana and Bessant, Christina M and Barton, Nick and Somers, Don and Barrett, John and Graves, Rebecca H and Hanns, Laura and Kerr, W. J. and Solari, Roberto (2013) Discovery of novel irreversible inhibitors of IL-2 inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket. Journal of Biological Chemistry (39). pp. 28195-28206. ISSN 1083-351X

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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.

ORCID iDs

Harling, John D, Deakin, Angela M, Campos, Sébastien, Grimley, Rachel, Chaudry, Laiq, Nye, Catherine, Polyakova, Oxana, Bessant, Christina M, Barton, Nick, Somers, Don, Barrett, John, Graves, Rebecca H, Hanns, Laura, Kerr, W. J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X and Solari, Roberto;