4M15

Crystal structure of ITK in complex with compound 9 [4-(carbamoylamino)-1-[7-(propan-2-yloxy)naphthalen-1-yl]-1H-pyrazole-3-carboxamide] and ADP

Summary for 4M15

• Entry DOI: 10.2210/pdb4m15/pdb
• Related: 4M0Y 4M0Z 4M12 4M13 4M14
• Descriptor: Tyrosine-protein kinase ITK/TSK, 4-(carbamoylamino)-1-[7-(propan-2-yloxy)naphthalen-1-yl]-1H-pyrazole-3-carboxamide, ADENOSINE-5'-DIPHOSPHATE, ... (4 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: 31429.58

Authors

Han, S.,Caspers, N.L. (deposition date: 2013-08-02, release date: 2014-04-02, Last modification date: 2024-02-28)

Primary citation

Han, S.,Czerwinski, R.M.,Caspers, N.L.,Limburg, D.C.,Ding, W.,Wang, H.,Ohren, J.F.,Rajamohan, F.,McLellan, T.J.,Unwalla, R.,Choi, C.,Parikh, M.D.,Seth, N.,Edmonds, J.,Phillips, C.,Shakya, S.,Li, X.,Spaulding, V.,Hughes, S.,Cook, A.,Robinson, C.,Mathias, J.P.,Navratilova, I.,Medley, Q.G.,Anderson, D.R.,Kurumbail, R.G.,Aulabaugh, A.
Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors.
Biochem.J., 460:211-222, 2014

PubMed Abstract: ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.

PubMed: 24593284
DOI: 10.1042/BJ20131139

Experimental method

X-RAY DIFFRACTION (1.52 Å)