4PPA

ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)

4PPA の概要

• エントリーDOI: 10.2210/pdb4ppa/pdb
• 関連するPDBエントリー: 4PP9 4PPB 4PPC
• 分子名称: Tyrosine-protein kinase ITK/TSK, N-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (2 entities in total)
• 機能のキーワード: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : Q08881
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61245.81

構造登録者

Eigenbrot, C.,Shia, S. (登録日: 2014-02-26, 公開日: 2014-06-04, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.67 Å)