Th2 cells are thought to play a central role in allergic asthma. The functional activity of the interleukin-2 inducible T cell kinase (ITK) is required for Th2 cytokine production. Therefore, inhibition of ITK activity is a promising strategy for treatment of allergic asthma.ITK is characterized by a high affinity for ATP (Km = 5 uM) which is expected to lead to a significant intracellular hurdle for ATP-competitive kinase inhibitors. We wish to present our strategy that targets ITK with covalent inhibitors to circumvent the biochemical efficiency hurdle inherent to the target. The covalent ITK inhibitors we are disclosing are the first reported in the literature. Low nanomolar enzyme potency of this series was achieved even in the presence of cellular ATP concentrations. Kinetic assessment confirmed an irreversible binding mode with off-rate half-lives well above 24 h and moderate on-rates. The analogs are very potent in a cellular IP1 biomarker assay as well as in a human whole-blood (hWB) assay.The half-life of ITK was determined to be approximately 2 hours in resting human primary CD4 T cells. However, covalent inhibition appears to stabilize ITK and the protein half-life increased to approximately 20 hours. Importantly, a prolonged pharmacodynamic effect was observed with inhibition of PLCg1 phosphorylation persisting for > 24 hours following stimulation of the T-cell receptor pathway. Based on this prolonged inhibitory effect, it was concluded that covalent inhibition is a viable strategy to target the inactivation of ITK.

Lessons learned from targeting interleukin-2 inducible T cell kinase (ITK) by a covalent approach

248th National Meeting (2014)

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