6PDJ

Tyrosine-protein kinase LCK bound to Compound 11

6PDJ の概要

• エントリーDOI: 10.2210/pdb6pdj/pdb
• 分子名称: Tyrosine-protein kinase Lck, N-{4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]-3-methylphenyl}-1-methyl-1H-indazole-3-carboxamide, 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID, ... (6 entities in total)
• 機能のキーワード: inhibitor, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34318.61

構造登録者

Critton, D.A. (登録日: 2019-06-19, 公開日: 2019-10-09, 最終更新日: 2024-10-30)

主引用文献

O'Malley, D.P.,Ahuja, V.,Fink, B.,Cao, C.,Wang, C.,Swanson, J.,Wee, S.,Gavai, A.V.,Tokarski, J.,Critton, D.,Paiva, A.A.,Johnson, B.M.,Szapiel, N.,Xie, D.
Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase.
Acs Med.Chem.Lett., 10:1486-1491, 2019

PubMed Abstract: C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead , and a series of modifications led to optimized compound . Compound showed potent activity in biochemical and cellular assays and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose.

PubMed: 31620238
DOI: 10.1021/acsmedchemlett.9b00354

実験手法

X-RAY DIFFRACTION (1.81 Å)