1407966-65-7Relevant articles and documents
Covalent inhibitors of interleukin-2 inducible T cell kinase (ItK) with nanomolar potency in a whole-blood assay
Zapf, Christoph W.,Gerstenberger, Brian S.,Xing, Li,Limburg, David C.,Anderson, David R.,Caspers, Nicole,Han, Seungil,Aulabaugh, Ann,Kurumbail, Ravi,Shakya, Subarna,Li, Xin,Spaulding, Vikki,Czerwinski, Robert M.,Seth, Nilufer,Medley, Quintus G.
, p. 10047 - 10063 (2013/01/16)
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.
