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Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay

2012; American Chemical Society; Volume: 55; Issue: 22 Linguagem: Inglês

10.1021/jm301190s

1520-4804

Christoph W. Zapf, Brian S. Gerstenberger, Xing Li, David C. Limburg, David R. Anderson, Nicole Caspers, Seungil Han, Ann Aulabaugh, Ravi G. Kurumbail, Subarna Shakya, Xin Li, Vikki Spaulding, Robert Czerwiński, Nilufer P. Seth, Quintus G. Medley,

Monoclonal and Polyclonal Antibodies Research

We wish to report a strategy that targets interleukin-2inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.