4HCT: Crystal Structure Of Itk In Complex With Compound 52

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.
PDB ID: 4HCTDownload
MMDB ID: 105091
PDB Deposition Date: 2012/10/1
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.48  Å
Source Organism:
Similar Structures:
Biological Unit for 4HCT: monomeric; determined by author and by software (PISA)
Molecular Components in 4HCT
Label Count Molecule
Protein (1 molecule)
Tyrosine-protein Kinase Itk/tsk(Gene symbol: ITK)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB