Summary
PDB 3FI2 deposited: 2008-12-10 modified: 2009-06-23
Title Crystal structure of JNK3 with amino-pyrazole inhibitor, SR-3451
Authors Chen, W., Duckett, D., Frackowiak, B., Habel, J., Jiang, R., Kamenecka, T., Ling, Y.Y., LoGrasso, P., Shin, Y., Song, X.
Method X-RAY DIFFRACTION
Structure factors resolution 2.28 rfactor 0.1805 rfree 0.2671
DPI 0.97 theoretical min: 0.30
Related PDB Entries 3FI3
Citations

c-Jun N-terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structure-based drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC(50) = 7 nm) with >2800-fold selectivity over p38 (p38 IC(50) > 20 microm) and had cell-based potency of approximately 1 microm. In contrast, indazole-based inhibitors exemplified by SR-3737 were potent inhibitors of both JNK3 (IC(50) = 12 nm) and p38 (IC(50) = 3 nm). These selectivity differences between the indazole class and the aminopyrazole class came despite nearly identical binding (root mean square deviation = 0.33 A) of these two compound classes to JNK3. The structural features within the compounds giving rise to the selectivity in the aminopyrazole class include the highly planar nature of the pyrazole, N-linked phenyl structures, which better occupied the smaller active site of JNK3 compared with the larger active site of p38.

J.Biol.Chem. 2009 May; 284(19):12853-12861 doi:10.1074/jbc.M809430200

Cross References
Database source Identifier Description
PubMed 19261605 JBCHA3
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3FI2/0 3FI2 0 monomer 0 1 2 2577