3FI3

Crystal structure of JNK3 with indazole inhibitor, SR-3737

Summary for 3FI3

• Entry DOI: 10.2210/pdb3fi3/pdb
• Related: 3FI2
• Descriptor: Mitogen-activated protein kinase 10, 3-{5-[(2-fluorophenyl)amino]-1H-indazol-1-yl}-N-(3,4,5-trimethoxyphenyl)benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: jnk3, protein-inhibitor complex, alternative splicing, atp-binding, chromosomal rearrangement, cytoplasm, epilepsy, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P53779
• Total number of polymer chains: 1
• Total formula weight: 42872.56

Authors

Habel, J.E.,Duckett, D.,LoGrasso, P. (deposition date: 2008-12-10, release date: 2009-03-03, Last modification date: 2023-09-06)

Primary citation

Kamenecka, T.,Habel, J.,Duckett, D.,Chen, W.,Ling, Y.Y.,Frackowiak, B.,Jiang, R.,Shin, Y.,Song, X.,LoGrasso, P.
Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-Jun N-terminal kinase 3 (JNK3) over p38.
J.Biol.Chem., 284:12853-12861, 2009

PubMed 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.

PubMed: 19261605
DOI: 10.1074/jbc.M809430200

Experimental method

X-RAY DIFFRACTION (2.2 Å)