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

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• 作者：Christoph W. Zapf ; Brian S. Gerstenberger ; Li Xing ; David C. Limburg ; David R. Anderson ; Nicole Caspers ; Seungil Han ; Ann Aulabaugh ; Ravi Kurumbail ; Subarna Shakya ; Xin Li ; Vikki Spaulding ; Robert M. Czerwinski ; Nilufer Seth ; Quintus G. Medley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10047-10063
• 全文大小：662K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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.