3V5J

Crystal Structure of Interleukin-2 Inducible T-cell Kinase Itk Catalytic Domain with Thienopyrazolylindole Inhibitor 090

3V5J の概要

• エントリーDOI: 10.2210/pdb3v5j/pdb
• 関連するPDBエントリー: 3V5L 3V8T 3V8W 3VF8 3VF9
• 分子名称: Tyrosine-protein kinase ITK/TSK, 3-[4-(2-morpholin-4-ylethoxy)-2-(1~{H}-thieno[3,2-c]pyrazol-3-yl)-1~{H}-indol-6-yl]pentan-3-ol, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61598.40

構造登録者

McLean, L.R.,Zhang, Y. (登録日: 2011-12-16, 公開日: 2012-05-02, 最終更新日: 2023-09-13)

主引用文献

McLean, L.R.,Zhang, Y.,Zaidi, N.,Bi, X.,Wang, R.,Dharanipragada, R.,Jurcak, J.G.,Gillespy, T.A.,Zhao, Z.,Musick, K.Y.,Choi, Y.M.,Barrague, M.,Peppard, J.,Smicker, M.,Duguid, M.,Parkar, A.,Fordham, J.,Kominos, D.
X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.
Bioorg.Med.Chem.Lett., 22:3296-3300, 2012

PubMed Abstract: Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.

PubMed: 22464456
DOI: 10.1016/j.bmcl.2012.03.016

実験手法

X-RAY DIFFRACTION (2.59 Å)