4HCT

Crystal structure of ITK in complex with compound 52

Summary for 4HCT

• Entry DOI: 10.2210/pdb4hct/pdb
• Related: 4hcu 4hcv
• Descriptor: Tyrosine-protein kinase ITK/TSK, 3-{1-[(3R)-1-acryloylpiperidin-3-yl]-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-(3-tert-butylphenyl)benzamide (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q08881
• Total number of polymer chains: 1
• Total formula weight: 31172.63

Authors

Zapf, C.W.,Gerstenberger, B.S.,Xing, L.,Limburg, D.C.,Anderson, D.R.,Caspers, N.,Han, S.,Aulabaugh, A.,Kurumbail, R.,Shakya, S.,Li, X.,Spaulding, V.,Czerwinski, R.M.,Seth, N.,Medley, Q.G. (deposition date: 2012-10-01, release date: 2012-11-14, Last modification date: 2024-02-28)

Primary citation

Zapf, C.W.,Gerstenberger, B.S.,Xing, L.,Limburg, D.C.,Anderson, D.R.,Caspers, N.,Han, S.,Aulabaugh, A.,Kurumbail, R.,Shakya, S.,Li, X.,Spaulding, V.,Czerwinski, R.M.,Seth, N.,Medley, Q.G.
Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay.
J.Med.Chem., 55:10047-10063, 2012

PubMed 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.

PubMed: 23098091
DOI: 10.1021/jm301190s

Experimental method

X-RAY DIFFRACTION (1.48 Å)