4PP9

ITK kinase domain with compound 1 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-2H-INDAZOLE-3-CARBOXAMIDE)

Summary for 4PP9

• Entry DOI: 10.2210/pdb4pp9/pdb
• Related: 4PPA 4PPB 4PPC
• Descriptor: Tyrosine-protein kinase ITK/TSK, SULFATE ION, N-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]-2H-indazole-3-carboxamide, ... (4 entities in total)
• Functional Keywords: protein kinase, phospho-transfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q08881
• Total number of polymer chains: 2
• Total formula weight: 61305.82

Authors

Eigenbrot, C.,Shia, S. (deposition date: 2014-02-26, release date: 2014-06-04, Last modification date: 2023-09-20)

Primary citation

Pastor, R.M.,Burch, J.D.,Magnuson, S.,Ortwine, D.F.,Chen, Y.,De La Torre, K.,Ding, X.,Eigenbrot, C.,Johnson, A.,Liimatta, M.,Liu, Y.,Shia, S.,Wang, X.,Wu, L.C.,Pei, Z.
Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.
Bioorg.Med.Chem.Lett., 24:2448-2452, 2014

PubMed Abstract: There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.

PubMed: 24767842
DOI: 10.1016/j.bmcl.2014.04.023

Experimental method

X-RAY DIFFRACTION (2.58 Å)