3FI2: Crystal Structure Of Jnk3 With Amino-Pyrazole Inhibitor, Sr- 3451

Citation:
Abstract
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.
PDB ID: 3FI2Download
MMDB ID: 69980
PDB Deposition Date: 2008/12/10
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.28  Å
Source Organism:
Similar Structures:
Biological Unit for 3FI2: monomeric; determined by author and by software (PISA)
Molecular Components in 3FI2
Label Count Molecule
Protein (1 molecule)
1
Mitogen-activated Protein Kinase 10(Gene symbol: MAPK10)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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