3KVX

JNK3 bound to aminopyrimidine inhibitor, SR-3562

3KVX の概要

• エントリーDOI: 10.2210/pdb3kvx/pdb
• 分子名称: Mitogen-activated protein kinase 10, N-[(2Z)-4-(3-fluoro-5-morpholin-4-ylphenyl)pyrimidin-2(1H)-ylidene]-4-(3-morpholin-4-yl-1H-1,2,4-triazol-1-yl)aniline (3 entities in total)
• 機能のキーワード: jnk3, mapk10, inhibitor, atp-binding, epilepsy, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P53779
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42694.38

構造登録者

Habel, J.E.,Laughlin, J.D.,LoGrasso, P. (登録日: 2009-11-30, 公開日: 2009-12-22, 最終更新日: 2023-09-06)

主引用文献

Kamenecka, T.,Jiang, R.,Song, X.,Duckett, D.,Chen, W.,Ling, Y.Y.,Habel, J.,Laughlin, J.D.,Chambers, J.,Figuera-Losada, M.,Cameron, M.D.,Lin, L.,Ruiz, C.H.,Lograsso, P.V.
Synthesis, Biological Evaluation, X-ray Structure, and Pharmacokinetics of Aminopyrimidine c-jun-N-terminal Kinase (JNK) Inhibitors
J.Med.Chem., 53:419-431, 2010

PubMed Abstract: Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors with good cell potency and good brain penetration properties. The structure-activity relationships (SAR) around a series of aminopyrimidines were evaluated utilizing biochemical and cell-based assays to measure JNK inhibition and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cell-based IC(50) values < 100 nM. Moreover, compound 9l showed an IC(50) = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rats along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.

PubMed: 19947601
DOI: 10.1021/jm901351f

実験手法

X-RAY DIFFRACTION (2.4 Å)