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Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-jun N-terminal kinase 3 (JNK3) over p38

Academic Article
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Overview

authors

  • Kamenecka, Theodore
  • Habel, J.
  • Duckett, Derek
  • Chen, W. M.
  • Ling, Y. Y.
  • Frackowiak, B.
  • Jiang, R.
  • Shin, Y. S.
  • Song, X. Y.
  • LoGrasso, Philip

publication date

  • May 2009

journal

  • Journal of Biological Chemistry  Journal

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.

subject areas

  • Activating Transcription Factor 2
  • Animals
  • Cells, Cultured
  • Crystallography, X-Ray
  • Enzyme Inhibitors
  • Humans
  • Insulin-Secreting Cells
  • Mitogen-Activated Protein Kinase 10
  • Models, Molecular
  • Phosphorylation
  • Protein Conformation
  • Pyrazoles
  • Rats
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases
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Identity

PubMed Central ID

  • PMC2676016

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M809430200

PubMed ID

  • 19261605
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Additional Document Info

start page

  • 12853

end page

  • 12861

volume

  • 284

issue

  • 19

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