title: Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor.
abstract: c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.
authors.affiliation: Infectious and Inflammatory Disease Center, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: Petra
authors.initials: P
authors.lastname: Pavlickova
authors.forename: Vida
authors.initials: V
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Machleidt
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Kuntzen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D016384:Consensus Sequence; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; D010455:Peptides; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases