3KVX: Jnk3 Bound To Aminopyrimidine Inhibitor, Sr-3562

Citation:
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.
PDB ID: 3KVXDownload
MMDB ID: 78980
PDB Deposition Date: 2009/11/30
Updated in MMDB: 2009/12
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 3KVX: monomeric; determined by author and by software (PISA)
Molecular Components in 3KVX
Label Count Molecule
Protein (1 molecule)
1
Mitogen-activated Protein Kinase 10(Gene symbol: MAPK10)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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