2. Academic Validation
  3. Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay

Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay

  • J Med Chem. 2012 Nov 26;55(22):10047-63. doi: 10.1021/jm301190s.
Christoph W Zapf 1,  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
Affiliations

Affiliation

  • 1 BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, USA. christoph.zapf@pfizer.com
PMID: 23098091 DOI: 10.1021/jm301190s
Abstract

We wish to report a strategy that targets interleukin-2 inducible 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.

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