title: Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-Jun N-terminal kinase 3 (JNK3) over p38.
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.
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Kamenecka
authors.forename: Jeff
authors.initials: J
authors.lastname: Habel
authors.forename: Derek
authors.initials: D
authors.lastname: Duckett
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Ling
authors.forename: Bozena
authors.initials: B
authors.lastname: Frackowiak
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.forename: Xinyi
authors.initials: X
authors.lastname: Song
authors.forename: Philip
authors.initials: P
authors.lastname: LoGrasso
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D048057:Mitogen-Activated Protein Kinase 10; D048051:p38 Mitogen-Activated Protein Kinases