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.
Structure factors resolution 2.28 rfactor 0.1805 rfree 0.2671
DPI 0.97 theoretical min: 0.30
Related PDB Entries 3FI3

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